Patent Docs

Platypus Genomic DNA Sequence Revealed

    By Kevin E. Noonan --

Ever since it was discovered by European explorers at the end of the 18th Century, the duckbill platypus (Ornithorhynchus anatinus) has been a biological anomaly.  Fur-bearing and lactating like a mammal (although lactation is through the abdominal wall because the animal lacks nipples), the platypus reproduces by egg-laying like a chicken and produces a venom like a reptile.  The platypus is so strange that George Shaw, who named the animal, thought it was a hoax:  he is reported to have said "[i]t was impossible not to entertain some distant doubts as to the genuine nature of the animal."  On Thursday, Nature reported the complete nucleotide sequencing of the platypus genome by an international team headed by scientists from Washington University/St. Louis (see "Top billing for platypus at the end of evolution tree").  Not surprisingly, the platypus' phenotypic peculiarities are reflected in its DNA, but the sequence promises to reveal a great deal more than that about the evolution of chickens, reptiles, and mammals, including man.

The sequencing experiments were performed using genomic DNA from one animal, obtained from the Glenrock Station at new South Wales, Australia (and nicknamed "Glennie").  It was known prior to sequencing that the platypus karyotype has 52 chromosomes, which is reported in Nature to comprise 2.3 billions basepairs of genomic DNA.  These chromosomes are morphologically characterized as comprising a few large chromosomes and several smaller ones, "reminiscent," according to the Nature report, "of reptilian macro- and microchromosomes."  Included in the chromosomal complement are multiple sex chromosomes, including five "X" and five "Y" chromosomes, which have been observed to properly segregate in sperm and egg cells.  In addition, these chromosomes have a certain level of homology to the "Z" sex chromosomes found in birds.

The sequencing efforts identified repetitive elements as well as putative protein-coding sequences.  The study of repetitive elements is informative in at least two ways.  First, the pattern and number of such elements provides a historical record of genetic events (such as retrovirus-mediated retrotransposition) that can be used to relate evolutionary events between different species of different phylogenies.  Second, at least some of these repetitive elements comprise structural or regulatory molecules (such as miRNA) that can be informative about genome structure as well as phylogenetic relationships.

Overall, the authors found fewer of the predicted non-protein coding RNA species than expected from mammalian species (1220 RNA species in the platypus compared with 4421 species in human and 655 in chicken).  On the other hand, the platypus shows amplification of small nucleolar RNA (snoRNA)-encoding sequences (2000 species in platypus compared with 200 in mammals); snoRNA is used in RNA modifications, particularly ribosomal RNA.  Notably missing in platypus genomic DNA are L1-retrotransposons, a feature in common with chickens, and notably present is a novel short interspersed (SINE) element present at about 40,000 copies.  The complexity of these SINE elements suggests a rapid and relatively recent genomic proliferation from an ancestral element.  Interspersed repetitive elements of all types comprise almost one-half of the platypus genome, the most abundant of which are a 5-kb long-interspersed-element (LINE2; about 1.9 million copies) and a "non-autonomous SINE-companion" interspersed repeat (about 2.75 million copies) that has been extinct in the other branches of the amniote phylogenetic line about 60-100 million years ago.  Finally, the mean microsatellite coverage in the platypus genome were estimated to be 2.67 +/- 0.34%, which is significantly lower than all mammalian genomes sequenced to date and most resembles what has been observed in chicken genomic DNA.

Protein-coding DNA was analyzed globally for comparison with mammalian DNA, and specifically to identify genes related to the aspects of platypus phenotype characteristic for features identified with its putative mammalian, avian, and reptilian roots.  Globally, the platypus genome encodes 18,527 protein-coding genes, which is similar to both humans and opossum.  The majority of these genes (15,312 out of 18,596, or 82%) have orthologous sequences in five other species for which comparisons were made (human, mouse, dog, opossum, and chicken).  Instances of simple 1:1 correspondence between platypus genes and orthologous genes in other species were enriched for so-called housekeeping genes, such as those involved in cellular metabolism, gene expression (especially mRNA splicing), and DNA replication.  However, although there was no correlation found in the position of such orthologous genes on the smaller platypus chromosomes and chicken microchromosomes, there was "considerable sequence alignment similarity" between the platypus "X" chromosomes and the chicken Z sex chromosome.  In contrast, there were no orthologous gene alignments observed when platypus sex chromosomes were compared to human X chromosomes.  The authors opine that this implied platypus X chromosomes evolved "directly from a bird-like ancestral reptilian system."

Turning to specific genes, the authors report results obtained for reproduction and lactation, chemosensory abilities, venom-producing genes, and cellular immunity.  The platypus genome contains four proteins homologous to human zona pellucida proteins, in addition to two genes (ZPAX) homologous to genes in birds, fish, and amphibians.  The platypus contains a single vitellogenin gene (chickens have three vitellogenin genes, while mammals have none), but lack testes-specific protease genes found in mammals.  Platypus milk is similar to mammalian milk, comprising sugars, lipids, and milk proteins with nutritional, anti-microbial, and bioactive functions.  Platypus casein genes, encoding the most abundant milk proteins (as in mammalian milk) are located in a syntenic position (adjacent to tooth enamel matrix protein genes) in platypus and mammalian chromosomes.

The platypus chemoreception system was found to be encoded by large numbers of genes encoding odorant receptors V1R and V2R, although the majority of these genes were genetically-inactivated pseudogenes.  The numbers of these genes were lower than those found in mammals (specific comparisons were made with rat and mouse); the odorant receptor gene complement was found to be about one-half that found in mammals.  However, the number of platypus V1R genes encoding an undisrupted open reading frame was about 50% higher than in mouse, and is the largest number of such genes yet detected in animal genomic DNA.  The genetic expansion of these specific receptors may, the Nature authors speculate, be the result of adaptations for pheromonal communication or detecting water-soluble odorants; this possibility is consistent with the animal's reliance on "smell" when underwater (since their other senses are muted in that environment).

Platypus venom is a complex mixture of at least 19 different peptides, including defensin-like peptides (vDLPs), C-type natriuretic peptide (vCNP) and nerve growth factor (vNGF).  Sequencing revealed that the genes encoding these various peptides appeared to have been produced from duplications of genes having different (i.e., non-venomous) functions.  The authors' analysis supported the conclusion that venom production comprising defensin, C-type natriuretic peptide, and nerve growth factor genes occurred independently in platypus and reptiles.

Finally, the platypus genome was remarkable for encoding at least 214 natural killer receptor genes, compared with human (15 genes), rat (45 genes), or opossum (9 genes) genomic DNA.  The platypus genome shares the feature of gene expansions in the cathelicidin antimicrobial peptide gene family with opossum genomic DNA.

The authors conclude that the homologies and differences between platypus genomic DNA and the sequences of the mammalian and other species observed by their comparisons support the hypothesis that the platypus lineage (the Monotrema) diverged from the rest of the eutherian lineage about 166 million years ago, and that the genetic distance of echidna (Tachyglossus aculeatus) from platypus . . . predicts that the platypus last shared a common ancestor with the other member of the Monotrema, the echidna, about 21 million years ago.

The authors express the hope that continued explication of the results of studies on platypus genomic DNA will contribute to a better understanding of the evolutionary relationship between mammals, including man, and other animals.  What is clear is that the relationships of the genes and other genetic elements found in platypus genomic DNA are consistent with descent with modification from a common ancestor guided by natural selection, and frankly inconsistent with "intelligent design" precepts.

A Future Genetic Tragedy?

    By Kevin E. Noonan --

In retrospect, it was eerily prescient.  The Wall Street Journal published an article Saturday, hours before the tragedy at Churchill Downs where Eight Belles, a two-year old filly was euthanized because she broke both front ankles after finishing second in the Kentucky Derby.  That article was about the danger to thoroughbred horses stemming from severe inbreeding over the past 50 years.

The problems stem from the racing success of the stallion Native Dancer, who was an ancestor of every one of the twenty horses running in this year's Derby.  And although this is the first time every horse in the race was related to this great progenitor horse, each of the last thirteen Derbys were won by one of his descendants.  In all, the article estimates that 75% of all U.S. thoroughbreds are related to Native Dancer.

The reason for the success of Native Dancer's line comes from the propensity for these horses to be "precocious" and "speedy," particularly at the age when they are running prestigious races like the Kentucky Derby.  But these positive attributes come with a "tragic flaw":  these horses have difficulties with their feet, most recently and tragically (before last Saturday) illustrated by last year's Kentucky Derby winner, Barbaro.  Barbaro won the Derby, but was injured during the running of the Preakness Stakes and ultimately euthanized after a valiant and public struggle to heal well enough to be put out to stud.  Barbaro was Native Dancer's great-great-great grandson.  Short racing careers (although rarely as tragic as Barbaro's) have been a characteristic of the Native Dancer line.

One reason for the excessive inbreeding to the Native Dancer line is that the overall number of stallions producing foals has dropped from 6,263 in 1992 to 3,083 in 2007, and the number of dams mated to each stallion last year was (on average) 60, up from 42 in 1998, according to the Journal.  The reason is economic:  using "established" or "proven" stallions increases the likelihood that the mating will produce a winner, and winners are what today's horse set wants.  Part of this is due to the transition of the horse-owning population from essentially rural owners with generations of tradition, to today's amalgam of "billionaire sheiks," entertainment figures and others with less interest in tradition than in profits.  This trend has been exacerbated by the increase in the prices paid for one-year olds, which last year was an average of $101,347.

The dangers of inbreeding have been known for many years with domestic animals, such as dogs and cats.  For example, Irish setters are prone to early blindness and Bernese Mountain dogs, a particularly popular breed, have a shortened life expectancy.  The problem threatens to become more pronounced as the products of genetic engineering are applied to animal breeding of farm animals.  The technology used to produce the cloned sheep Dolly is being used to clone a prize bull, a holy grail of animal breeders since Clement Markert produced a triple allophenic mouse at Yale thirty years ago.  (Markert's student, Jon Gordon, produced the first transgenic mouse a few years later in Frank Ruddle's lab.)

Yet such animals threaten to have an even greater, and much more rapid, effect on genetic diversity than Native Dancer.  Although Native Dancer is an ancestor of a great many of today's thoroughbreds, each generation involved crosses of animals merely related to Native Dancer and thus carrying at least a portion of their genetic complement from other lines.  A Native Dancer clone, on the other hand, would effect transfer of the same genes in every mating, and the risks of producing unexpected and deleterious mutations or variants, or combinations thereof, are incalculable.  It is significant in this regard to recall that the cheetah population, one of the most endangered of the large cats, is particularly at risk because their population went through a "bottleneck" about 10,000 years ago, making all living cheetahs distant cousins (see "Tears of the Cheetah" by Steve O'Brien).

Ironically, Eight Belles was only distantly-related to Native Dancer:  her father, Mr. Prospector, was the sire of her dam's dam with no other Native Dancer relatives in her immediate pedigree.  It is impossible to know whether Eight Belles' fate was related to her genetic heritage.  But it is also impossible to establish that it was not, raising the specter of some type of genetic deficiency (e.g., susceptibility to diseases) that may threaten food production in ways that could dwarf the fears attendant to the current transgenic animal and crops debate.

Who’s to Blame for Rising Drug Prices?

    By Kevin E. Noonan --

Gina Kolata identifies the villain of her recent piece in The New York Times on rising drug costs in the first sentence:  "[h]ealth insurance companies" that have changed their reimbursement and prescription drug coverage for certain high-priced drugs (see "Co-Payments Soar for Drugs With High Prices").  But that didn't keep the Times from trying to use the story to further its anti-innovation agenda.

As Ms. Kolata explains, several of the country's largest medical insurance companies have changed their policies to dramatically increase the co-payment costs for some drugs.  These drugs, termed "Tier 4" drugs, typically have much higher costs than conventional drugs, and are prescribed for chronic and serious diseases, like "multiple sclerosis, rheumatoid arthritis, hemophilia, hepatitis C and some cancers."  These drugs are usually the only drugs available to treat these patients, and their costs can be astronomical for the typical patient (up to $100,000 annually).  Instead of co-payments of $10-20 per prescription, the article cites co-payment costs of $325 to 4,000, which force patients to "spend more for a drug than they pay for their mortgages, more, in some cases, than their monthly incomes."

The Tier 4 regime started in the Medicare program, and now 86% of those plans have adopted Tier 4 pricing (and there is another level, Tier 5, that is even more expensive), according to Mr. Kolata.  The reason, of course, is curbing costs, and the economic imperatives in Medicare programs are now extending to private medical plans.  For example, insurance companies are offering this option to employers as a way to reduce plan costs and to reduce the costs of insurance, and drug co-payments, for patients needing less-expensive drugs.  Ten percent of private insurance now uses the Tier 4 system.

However, this strategy turns the traditional calculus of medical insurance (indeed, all insurance) on its head.  Insurance has always been based on the model of taking relatively modest premiums from the many to pay the costs of the few that (at any particular time) are entitled to benefits.  James Robinson, a health economist at the University of California, Berkeley, is quoted in the article:  "It is very unfortunate social policy.  The more the sick person pays, the less the healthy person pays."  "This is an erosion of the traditional concept of insurance," said Dan Mendelson of Avalere Health, a research organization in Washington, "[t]hose beneficiaries who bear the burden of illness are also bearing the burden of cost."

The article specifically relates the stories of three drugs impacted by the new program, including Copaxone® (generic name, glatiramer acetate) from Teva Pharmaceuticals, for multiple sclerosis:

Sprycel® (generic name, dasatinib) from Bristol-Myers Squibb, for chronic myelogenous leukemia:

and Tykerb® (generic name, lapatinib) from Glaxo-Smith Kline, for metastatic breast cancer, comprising a random polymer of 4 amino acids from myelin basic protein.  In a sidebar to the story are other Tier 4 drugs, including biotechnology drug products such as Humira®, Cerezyme®, Procrit®, and Neupogen®.

And that, it appears, is all the Times editorial board could think about when deciding the "Paper of Record's" official position.  While properly decrying the insurance industry's shifting of the cost of these treatments onto the patients who were forced to take (and pay for) them, the Times couldn't help reminding us of their anti-technology position.  In an editorial published on Tuesday (see "When Drug Costs Soar Beyond Reach"), the Times ignored the facts presented in Ms. Kolata's article, that the reason for the increased drug pricing was economic, and found the real culprits:

The drug companies, especially the biotechnology companies, are at the root of the problem; they often charge exorbitant prices for monopoly drugs that were developed with heavy government assistance.  Washington needs to rein them in by encouraging generic competition for biological drugs and allowing government programs to negotiate lower prices.

The statement repeats the familiar canards that the uninformed and willfully ignorant bandy about in demonizing biotechnology companies.  The costs of bringing a biotechnology drug to market can be hundreds of millions of dollars, and that cost is not borne by the government or defrayed by "heavy government assistance."  That assistance, which is parceled out in competitive grants to universities, or to small businesses, is given not to produce drugs but to further research and development; drug discovery is a happy and beneficial consequence.  The Times has no evidence, certainly not from Ms. Kolata's article, that the prices for these lifesaving drugs are "exorbitant" or anything more than what is necessary to defray the "exorbitant" costs of developing these drugs in the first place.  And as the Times well knows, a large portion of these costs are incurred fulfilling the regulatory requirements of the Food and Drug Administration.  Of course, there are alternatives, including reduced regulatory scrutiny for new drugs, but that is a cost we as a society do not care to shift from the drug companies to patients.

Ms. Kolata's article mentions that Kaiser Permanente, one of the largest health insurers having policies covering Federal employees and their families, has decided to suspend the Tier 4 system for 2008 and to refund the excess co-payments to their insureds while the company reconsiders its policies (at least for Federal employees in the mid-Atlantic region).  This turnaround shows that Kaiser has the capacity to re-evaluate its position when it has evidence that it has made a mistake.  Unfortunately, on the evidence of the Times' persistent anti-technology stance, it does not have (or is unwilling to exercise) the same ability.

Antigenics Announces First-Ever Approval for "Personalized" Cancer Treatment

    By Mark Chael --

On April 8th, Antigenics Inc. announced that the Russian Ministry of Public Health had approved Oncophage® for the treatment of intermediate-risk kidney cancer.  According to Antigenics, Oncophage® is derived from a discrete tumor and contains the antigenic fingerprint of the cancer cells that make up that particular tumor, making Oncophage® "personalized" to fight against recurrence of the tumor.  Treatment with Oncophage® after full or partial removal of a tumor is designed to reprogram the body’s immune system to attack remaining cancer cells and new cancer cells with the corresponding antigenic fingerprint.

The company has over 50 U.S. patents covering the Oncophage® platform technology, including U.S. Patent No. 7,309,491, and no doubt a number of pending patent applications worldwide.

According to some reports, Oncophage® failed to lower the overall risk of relapse in a Phase III trial, but it helped 60 percent of people stay in remission longer if they had an intermediate risk of recurrence.  This treatment has received fast track and orphan drug designations from the U.S. Food and Drug Administration (FDA) for both kidney cancer and metastatic melanoma, but it has yet to be fully approved for use anywhere outside of Russia.  The company plans on seeking European approval later this year and is in ongoing discussions with the FDA for approval in the U.S.

Oncophage®, also called vitespen and formerly called HSPPC-96, is derived from proprietary heat shock protein technology developed at Antigenics and elsewhere.  The personalized cancer vaccine is generated after full or partial resection of a tumor, which is then shipped to Antigenics for processing.  At Antigenics, heat shock protein gp96 and associated peptides are isolated from the tumor and processed for re-introduction into the patient as a putative cancer vaccine.  If successfully prepared from the tumor, the vaccine is normally ready for injection into the patient within 6 to 8 weeks following surgery.

Antigenics is publicly traded on the NASDAQ exchange under the symbol AGEN.

StemCellPatents.com Launches New Stem Cell Patent Database

    By Donald Zuhn --

StemCellPatents.com has announced the launch of a newly redesigned stem cell patent database.  A beta version of the database was launched in November 2006.  The stem cell patent database will extend the site's other offerings, which include online news, a weekly e-mail newsletter, the SCP Journal, and a jobs board.

According to a BusinessWire report, the new database contains "comprehensive summaries and analysis of over 1200 patents hand-picked by experts in the field to be of relevance to stem cell commercialization and development."  As of Thursday, the stem cell patent database included summaries and bibliographic information for 1,269 U.S. patents relating to stem cells.

Dr. Vladimir Bogin, and member of the site's advisory board and a principle of Cromos Pharma Services, observed that while the media has lately focused its attention on WARF's embryonic stem cell patents, the "minefield of issued patents in the area of stem cell therapy" has been grossly underestimated by the industry.  Dr. Bogin noted that by compiling the stem cell patent database, the website hoped to let investigators know "what is out there and what is not, with the hope of accelerating commercialization and, in turn, progress."  Other members of the site's advisory board include Don McAdam, the CEO of MBVax Corporation, and Dr. Zhoahui Zhong, a Professor of Medicine at that Hunan Medical University in Changsha, China.

New Follow-on Biologics Bill Introduced in the House

    By Donald Zuhn --

Last Thursday, Rep. Anna Eshoo (D-CA; at right) introduced a new biologics bill in the House.  The bill (H.R. 5629), which would amend Section 351 of the Public Health Service Act to create a regulatory pathway for biosimilars, has been referred to the Committee on Energy and Commerce and the Committee on the Judiciary for consideration.

Rep. Eshoo's bill would specify an exclusivity period of 12 years (i.e., a generic company would have to wait 12 years after the innovator biologic is first licensed before the generic's own follow-on biologics application could be approved).  The exclusivity period specified in H.R. 5629 can be contrasted with that of H.R. 1956, which was introduced by Rep. Jay Inslee (D-WA) last April, and which specifies a 14 year period of exclusivity for the innovator product.

We first learned of Rep. Eshoo's bill last month during a conference call with Biotechnology Industry Organization (BIO) President and CEO Jim Greenwood (at left) (see "BIO CEO Provides Update on Patent Reform and Follow-on Biologics Legislation - Part II").  During the conference call, Mr. Greenwood expressed a preference for Rep. Inslee's bill, in part because the details of Rep. Eshoo's bill were not yet known.

On Friday, BIO released a statement regarding Rep. Eshoo's bill, in which Mr. Greenwood commended Rep. Eshoo and Rep. Joe Barton (R-TX), a co-sponsor of the bill and the top Republican on the House Energy and Commerce Committee, for "taking a strong, bipartisan step forward toward developing a pathway for the approval of follow-on biologics."  Mr. Greenwood noted that the regulatory pathway defined by H.R. 5629 contained "essential elements" needed to protect patient safety and ensure continued innovation.  Among these essential elements are provisions of the bill that call for generic companies to submit clinical and immunogenicity studies, and that allow the FDA to make determinations on the interchangeability of follow-on biologics.

While Mr. Greenwood observed that Rep. Eshoo's bill "falls short of the base 14 years that has been demonstrated to be the needed period required to strike the right balance between providing incentives for innovation and follow-on product entry," he urged Congress to "pass the right bill as soon as possible."  (Mr. Greenwood did not specify which of the two bills was the "right" one, but one presumes he would favor the 14 year exclusivity period of H.R. 1956.)  Arguing that it was "time to place patient needs before political gamesmanship," Mr. Greenwood called for passage of a "pro-patient, pro-innovation, pro-science follow-on biologics bill."

One of The Wall Street Journal blogs also chimed in last Friday concerning H.R. 5629.  Unfortunately, the Journal got a few things about the bill wrong.  First, the Journal reported that the exclusivity period in the Eshoo bill was 14.5 years, rather than 12 years.  Second, the article appears to have implied that the exclusivity period would run from the time the bill became law, rather than from the time the innovator biologic was approved for use.  A clarification was subsequently added to the article after its author received word from Rep. Eshoo's Chief of Staff regarding the errors.

For additional information on this and other related topics, please see

• "BIO CEO Provides Update on Patent Reform and Follow-on Biologics Legislation - Part II," February 14, 2008
• "Insmed Announces National Awareness Campaign Regarding Follow-on Biologics," February 13, 2008
• "Millennium Pharmaceuticals Spent $1.28 Million on Lobbying in 2007," February 8, 2008
• "Biologics Legislation Faces Unresolved Issues," December 28, 2007
• "BIO CEO Provides Briefing on Follow-On Biologics and Patent Reform," September 18, 2007
• "Biotechs Facing New Challenges," August 13, 2007
• "Three New Biosimilars Pass EMEA Test," July 26, 2007
• "European Medicines Agency Releases Paper on Biosmiliar Medicines," July 23, 2007
• "Senate Committee Passes Biologics Legislation," July 5, 2007

Yes, It IS Time (Finally) to Stop the Hypocrisy over Human Stem Cell Patents

    By Kevin E. Noonan --

The two remaining ex parte re-examinations (35 U.S.C. § 302-307) of Wisconsin Alumni Research Foundation (WARF) stem cell patents -- Control No. 90/008102 for U.S. Patent No. 5,843,780 (claiming primate embryonic stem (pES) cells) and Control No. 90/008139 for U.S. Patent No. 6,200,806 (claiming human embryonic stem cell (hES) cells) -- have been decided, and the U.S. Patent and Trademark Office has determined that the claims of these patents are patentable, after all.  These decisions are a stunning victory for WARF, and a crushing defeat for the Public Patent Foundation (PUBPAT), headed by Dan Ravicher, and the Foundation for Taxpayer and Consumer Rights (FTCR), a California taxpayer group (which recently became ConsumerWatchdog.org).

Unlike the 85-page decision announcing the patentability of WARF's U.S. Patent No. 7,029,913 in an inter partes re-examination (35 U.S.C. § 311-318) proceeding (see "(Finally) It May Be Time to Stop the Hypocrisy over Stem Cell Patents"), the Office dispensed with these two challenges much more parsimoniously.  In re-examination of the '780 patent, the original grounds of rejection asserted by the Examiner were as follows:

• That claims 1-11 were unpatentable under 35 U.S.C. § 102(b) for being anticipated by U.S. Patent No. 5,166,065 to Williams.
• That claims 1-8 and 11 were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the '065 patent.
• That claims 1-8 were unpatentable under 35 U.S.C. § 102(b) for being anticipated by U.S. Patent No. 5,690,926 to Hogan.
• That claims 1-8 were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the '926 patent.
• That claim 11 was unpatentable under 35 U.S.C. § 102(b) for being anticipated by Bongso et al., 1994, Hum. Reprod. 9: 2110-17 (see "WARF Responds to the Patent Office on Its Re-examined Stem Cell Patents").
• That claim 11 was unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Bongso reference.
• That claims 1-11 were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of Robertson '83 (Cold Spring Harbor 10: 647-63), the Robertson '87 reference (Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, IRL Press), or Piedrahita et al., 1990, Theriogenology 34: 879-901, taken alone or in combination with the '065 and '926 patents.

In the communication mailed on Tuesday, all these grounds of rejection were withdrawn and the claims as amended by the patentee were deemed patentable.  Amended claims 1, 3, 9 and 11 and added new claims 12-14 read as follows:

1.  A purified preparation of pluripotent primate embryonic stem cells derived from preimplantation embryos wherein the stem cells (i) will proliferate in an in vitro culture for over one year in an undifferentiated state, (ii) maintain a karyotype in which all the chromosomes characteristic of the primate species are present and not noticeably altered through prolonged culture, (iii) maintain the potential to differentiate into derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) will not differentiate when cultured on a fibroblast feeder layer.

3.  A purified preparation of primate embryonic stem cell line wherein the cells of the cell line are negative for the SSEA-1 marker, positive for the SSEA-3 marker, positive for the SSEA-4 marker, express alkaline phosphatase activity, are pluripotent, and have karyotypes which includes the presence of all of the chromosomes characteristic of the primate species and in which none of the chromosomes are noticeably altered.

9.  A method of isolating a pluripotent primate embryonic stem cell line, the method comprising the steps of:
    (a) isolating a primate blastocyst;
    (b) isolating cells from the inner cell mass of the blastocyst of (a);
    (c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell mass-derived cells masses are formed;
    (d) dissociating the mass into dissociated cells;
    (e) replating the dissociated cells on embryonic feeder cells;
    (f) selecting colonies with compact morphologies and cells with high nucleus to cytoplasm ratios and prominent nucleoli; and
    (g) culturing the cells of the selected colonies to produce an isolated pluripotent primate embryonic stem cell line that is capable of proliferating as undifferentiated cells for over one year.

11.  A cell line that is capable of proliferation for over one year developed by the method of claim 9.

12.  A method of isolating a pluripotent primate embryonic stem cell line, the method comprising the steps of:
    (a) isolating a primate blastocyst;
    (b) isolating cells from the inner cell mass of the blastocyst of (a);
    (c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell mass-derived cells masses are formed;
    (d) dissociating the mass into dissociated cells;
    (e) replating the dissociated cells on embryonic feeder cells;
    (f) selecting colonies with compact morphologies that are flatter than mouse embryonic stem cell colonies, wherein the cells with high nucleus to cytoplasm ratios and prominent nucleoli; and
    (g) culturing the cells of the selected colonies to produce an isolated pluripotent primate embryonic stem cell line that is capable of proliferating as undifferentiated cells for over one year.

13.  A method as claimed in claim 12, further comprising maintaining the isolated cells on a fibroblast feeder layer to prevent differentiation.

14.  A cell line that is capable of proliferation for over one year as undifferentiated cells developed by the method of claim 12.

The Examiner made these determinations in the Statement of Reasons for Patentability:

U.S. Patent No. 5,166,056 to Williams does not anticipate the '780 patent claims because the Williams patent disclosed only mouse ES cells and did not inherently enable the hES cells claimed in the '780 patent.  Moreover, any implied teaching with regard to hES cells was contradicted by a later paper (Cherny and Williams, 1994, Reprod. Fert. Develop. 6: 569-75), stating that the methods of isolating mouse embryonic stem cells "would not extend" to methods for isolating human pluripotent ES cells.  The Williams '065 patent also did not disclose primate ES cells that differ from mouse ES cells in the expression of markers like SSEA-1, nor do the mouse ES cells differentiate into trophoblast when induced to differentiate.  The Williams '065 patent was limited to mouse ES cells.  Moreover, the Examiner believed that undue experimentation would be required to practice the methods of the Williams patent to produce hES cells, since there could be no reasonable expectation of success in view of all of the evidence of record.

Turning to the '926 patent, the Examiner determined that the EG cells disclosed by Hogan are distinct from the ES cells claimed in the '780 patent, because: (1) they were derived from post-implantation embryos; (2) the Hogan EG cells are SSEA-1 positive; and (3) the Hogan EG cells do not differentiate into trophoblast when differentiation is induced.  The Examiner, therefore, found that the '926 patent neither anticipates nor renders obvious the claims of the 780 patent.  In addition, the methods used by Hogan would not render obvious the ES cells obtained from pre-implantation embryos.  Finally, the Examiner found that the degree of unpredictability in producing hES cells having the properties of the hES cells claimed in the '780 patent precluded the reasonable expectation of success required to support an obviousness determination.

The Examiner determined that the Bongso reference (Ariff Bongso at right) did not teach pluripotent embryonic stem cells that proliferate for over one year in an undifferentiated state (noting that the cells produced by Bongso either differentiated into fibroblasts or died after the second culture passage), nor did they exhibit the other characteristic features of the hES cells claimed in the '780 patent.  Moreover, a Declaration from the '780 patent inventor, James Thomson, established that Thomson had invented his ES cells prior to the November 1994 publication date of the Bongso reference.

Finally, the Examiner considered whether the combination of the Robertson '83 reference, the Robertson '87 reference, or the Piedrahita reference, either alone or in combination with the '065 patent and the '926 patent, rendered the '780 patent obvious.  He found that while the two Robertson references disclosing mouse ES cells taught methods for producing mouse ES cells, the Piedrahita reference failed to isolate ES cells from pigs or sheep and showed that the methods used to produce mouse ES cells were not applicable to other mammals and indeed, taught away from applying techniques used in mice in other mammals.  The combination thus did not render obvious the claims of the '780 patent.  The Examiner came to the same conclusion with regard to the combination of these references with the teachings of the '065 patent and the '926 patent.

In re-examination of the '806 patent, the Robertson '83, Robertson '87, Piedrahita, and Bongso references, and Williams '065 and Hogan '926 patents were applied to the claims, as well as U.S. Patent 5,453,357 to Hogan; Behrouz et al., 2005 (Current Opinion in Biotechnology 16: 530-535), and Cruz et al., 1991 (Current Communications 4: 147-204).  The Notice expressly defined the terms "stem cells," "embryonic stem cells," "pluripotent," and "true ES cells."

With respect to the '806 patent, the Examiner withdrew the following grounds of rejection:

• That claims 1-8 and 11 were unpatentable under 35 U.S.C. § 102(e) for being anticipated by the '926 or '357 patents alone, or as further evidenced by the '806 patent disclosure demonstrating inherency.
• That claim 11 was unpatentable under 35 U.S.C. § 102(a) for being anticipated by the Bongso reference.
• That claim 11 was unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Bongso reference.
• That claims 1-11 were unpatentable under 35 U.S.C. § 102(b) for being anticipated by the '065 patent.
• That claims 1-11 were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the '065 patent.
• That claims 1-11 were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Robertson '83 reference, Robertson '87 reference, or Piedrahita reference, taken alone or in combination with the '065 and '926 patents.

The amended claims of the '806 patent read as follows:

1.  A purified preparation of pluripotent human embryonic stem cells derived from preimplantation embryos wherein the stem cells (i) will proliferate in an in vitro culture for over one year in an undifferentiated state, (ii) maintain a karyotype in which the chromosomes are euploid and not altered through prolonged culture, (iii) maintain the potential to differentiate into derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) are inhibited from differentiation when cultured on a fibroblast feeder layer.

3.  A purified preparation of primate embryonic stem cell line wherein the cells of the cell line are negative for the SSEA-1 marker, positive for the SSEA-3 marker, positive for the SSEA-4 marker, express alkaline phosphatase activity, are pluripotent, and have euploid karyotypes and in which none of the  chromosomes are altered.

9.  A method of isolating a pluripotent primate embryonic stem cell line, comprising the steps of:
    (a) isolating a human blastocyst;
    (b) isolating cells from the inner cell mass of the blastocyst of (a);
    (c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell mass-derived cells masses are formed;
    (d) dissociating the mass into dissociated cells;
    (e) replating the dissociated cells on embryonic feeder cells;
    (f) selecting colonies with compact morphologies and cells with high nucleus to cytoplasm ratios and prominent nucleoli; and
    (g) culturing the cells of the selected colonies the thereby obtain an isolated pluripotent human embryonic stem cell line that is capable of proliferation as undifferentiated cells for over one year.

11.  A cell line that is capable of proliferation for over one year developed by the method of claim 9.

12.  A method of isolating a pluripotent human embryonic stem cell line, the method comprising the steps of:
    (a) isolating a human blastocyst;
    (b) isolating cells from the inner cell mass of the blastocyst of (a);
    (c) plating the inner cell mass cells on embryonic fibroblasts, wherein inner cell mass-derived cells masses are formed;
    (d) dissociating the mass into dissociated cells;
    (e) replating the dissociated cells on embryonic feeder cells;
    (f) selecting colonies with compact morphologies that are flatter than mouse embryonic stem cell colonies, wherein the cells with high nucleus to cytoplasm ratios and prominent nucleoli; and
    (g) culturing the cells of the selected colonies to produce an isolated pluripotent human embryonic stem cell line that is capable of proliferating as undifferentiated cells for over one year.

13.  A method as claimed in claim 12, further comprising maintaining the isolated cells on a fibroblast feeder layer to prevent differentiation.

14.  A cell line that is capable of proliferation for over one year as undifferentiated cells developed by the method of claim 12.

The Examiner found that neither the Hogan '926 nor Hogan '357 patents taught hES cells that did not express SSEA-1 on the cell surface, were derived from preimplantation embryos or could be derived from human blastocysts.  The inherent expression of SSEA-1 was considered a marker that the hES cells claimed in the '806 patent were patentably distinct from Hogan's EG cells.  The Examiner cited the Behrouz reference in support of this distinction.  The Examiner also found that the Bongso reference did not anticipate Claim 11, since Bongso's cells had none of the proliferation properties of the hES cells encompassed by the claims.  In addition, a Declaration by the inventor established an earlier date of invention prior to the publication date of the Bongso reference.

Turning to the Williams '065 patent, the Examiner found that both the prosecution history of the patent (wherein the Examiner had required Williams to limit the claims from "animal" ES cells to mouse ES cells), and the Cherney-Williams reference showed that the Williams '065 patent was not enabling for the hES cells claimed in the '806 patent.  Finally, the Examiner determined that the combination of the Robertson '83 reference, Robertson '87 reference, or Piedrahita reference, taken alone or in combination with the '065 and '926 patents did not "engender a reasonable expectation of success" in producing the hES cells claimed in the '806 patent.

The Examiner also expressly set forth the evidence for and against a prima facie obviousness case originally raised against the '806 patent claims.  On the side of non-obviousness, the Examiner found that "the prior art of record neither discloses nor contained an enabling suggestion of how to make true hES cells or cell lines without the necessity for undue experimentation."  Thus, despite a high level of ordinary skill in the art, "there was no reasonable expectation of successfully isolating true hES cells or cell lines" using methods successful in mice, "given the highly unpredictable nature of the prior art."

The Examiner noted that as of the priority date of the '806 application (January 20, 1995), no one had reported isolating a hES cell line, despite the fact that rodent (mouse, hamster, and rat) ES cell lines had been isolated and their properties characterized.  The Examiner also noted the unique features of the hES cells claimed in the '806 patent:  permanent, euploid, embryo-derived cell lines that could differentiate into all three embryonic germ cell layers.  The Examiner also cited the combination of the success taught by the Robertson references with regard to mouse ES cells, and the failures described in the Piedrahita reference in attempting to apply these teachings to ES cells from other mammalian species.  The Examiner cites the Cruz reference on the differences between ES cells from different mammalian species, which supports the non-obviousness determination.  Finally, the Examiner uses the Hogan '926 patent as evidence that the art recognized the difficulty in producing hES cells, and thus turned to primordial germ cells (EG cells) as an alternative.

The Examiner also cited the evidence of failure of others and the "wide acclaim" Dr. Thomson received from his peers as objective indicia of non-obviousness.

The evidence supporting the obviousness determination, on the other hand, was principally the declaration submitted by Dr. Jeanne Loring (see "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part III").  In addition, Professor Loring (at right) testified to conversations with Dr. Hogan and Dr. Iannaccone "regarding putative or actual attempts at obtaining hES cells from blastocysts using the same techniques disclosed in the Robertson references" relating to mouse ES cells.  The Examiner opined that "little weight" should be given Dr. Loring's declaration evidence "since it states opinion on the ultimate legal issue [obviousness] without providing sufficient underlying factual support."  The Examiner also gave little weight to the "uncorroborated conversations" Dr. Loring putatively had with other experts, "when considered in light of all the documentary evidence of record."

Balancing the factual evidence, the Examiner concluded that the '806 patent claims were not obvious.

These decisions cannot be appealed by the third party requestor, since their active involvement ended when the ex parte re-examination was declared (although they were served with all papers between the Patent and Trademark Office and WARF during the pendency of the re-examination).  Since neither PUBPAT nor FTCR are practicing the claimed invention, they have no standing to ask a District Court for a declaratory judgment of invalidity, and such a judgment should only be harder to obtain in view of the results of these re-examinations.

This is good news for WARF and Professor Thomson, who can now get back to his research on making pluripotent stem cells from fibroblasts, a more robust and less ethically and politically controversial procedure.  After trumpeting as victories the initial (and expected) Office Action rejections issued by the Patent Office in these re-examinations, perhaps PUBPAT and FTCR will be more prudent and circumspect about the "bad" patents it chooses to attack.  After all, they have to be out there, don't they?

For information regarding this and other related topics, please see:

• "(Finally) It May Be Time to Stop the Hypocrisy over Stem Cell Patents," February 28, 2008
• "WARF Licenses Stem Cell Patent Portfolio to BioTime," January 23, 2008
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part III," July 4, 2007
• "WARF Responds to the Patent Office on Its Re-examined Stem Cell Patents," June 26, 2007
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part II," April 26, 2007
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part I," April 17, 2007
• "WARF Stem Cell Patent Claims Rejected in Re-examination," April 3, 2007

Thailand Continues Its Compulsory Licensing Practices

    By Kevin E. Noonan --

Any hopes that Thailand would amend or overrule its policy of ignoring drug patent rights were dashed when the Thai government announced that it intended to maintain its extension of its compulsory licensing policy to four anti-cancer drugs:  Novartis' Imatinib® and Letrozole®, Sanofi-Aventis' Docetaxel®, and Roche's Erlotinib®.  The motivation is clear -- these compulsory licenses are estimated to save Thailand more than 3 billion baht ($100 million) over the next five years.

These actions are consistent with previous compulsory licenses granted on anti-AIDS drugs, including Abbott's Aluvia®, a heat-stable formulation of Kaletra® (see "Pharma Sanity Lacks Global Reach"), as well as Novartis' anti-leukemia drug Glivec®; ironically, the compulsory license on Glivec® was cancelled when Novartis agreed to supply the drug free to Thai patients.  These activities have been met with strong condemnation from the U.S., which placed Thailand on its "priority watch list" in its Special Section 301 Report last May (see "Worldwide Drug Pricing Regime in Chaos"), and the European Union, where Trade Commissioner Peter Mandelson demanded Thailand stop its compulsory licensing program (see "EU Trade Commissioner Sends Warning Letter to Thailand").

All this is occurring against a backdrop of political turmoil in the Thailand government's regulatory ranks.  Last week, Chatree Banchuen, only recently appointed the head of Thailand's Food and Drug Administration, resigned over the issue.  His predecessor, Siriwat Thiptharadon, was the architect of the latest scheme to grant compulsory licenses on the four drugs, and has charged that his demotion to an inactive government post was caused by his anti-patent stance.  The new Thai Public Health Minister, Chaiya Sasomsup, affirmed that compulsory licenses would be maintained unless Thailand was successful in negotiating an "affordable price" for the drugs.  And these actions seems to validate comments from the Thai Public Health Minister, Mongkol Na Songkhla, that indicate that Thailand will further expand this category for all "essential" drugs needed to support the government's universal health care plan.

The opposition (such as it is) within the Thai government is based in part on apprehension that the U.S. or EU would impose trade sanctions on Thailand in response to compulsory licensing.  However, the provisions of the Doha Declaration have made the success (and legality) of such sanctions less likely.

Of course, some in the Thai government say the drug companies only have themselves to blame.  Suwit Wibulpolprasert (at left), a senior adviser on disease control at the Thai Ministry of Public Health, alleges that Western drug companies refused to negotiate with the Thai government until they were threatened with compulsory licenses.

The abiding irony is that the very international agreements intended to increase intellectual property rights in countries like Thailand have instead provided such countries with all the promised protections for their own industries while permitting these countries to violate patent protection for a wide range of pharmaceuticals.  Prudence suggests that Western drug companies and their governments come up with a strategy that will accommodate the companies' legitimate interest in protecting their intellectual property and investment in these drugs while at the same time recognizing the political and economic pressures on countries like Thailand to take advantage of the provisions of GATT and the WTO that make these drugs affordable.  That has not happened yet, and with the tide turning towards more countries using these treaty provisions (notably, the Doha Declaration) to grant compulsory licenses and parallel importing for more drugs for treating more diseases, it can't come soon enough.

For information regarding this and other related topics, please see:

• "Neocolonialism in the Current Global Drug Pricing Regime?" August 19, 2007
• "More on the Global Drug Patenting Crisis," August 14, 2007
• "EU Trade Commissioner Sends Warning Letter to Thailand," August 13, 2007
• "Trying to Find a Solution to the Global Drug Pricing Crisis," July 16, 2007
• "Pharma Sanity Lacks Global Reach," July 13, 2007
• "Brasil Prevails in Dispute with Abbott over AIDS Drug Pricing," July 9, 2007
• "Africa (Still) Depending on the Kindness of Strangers in Anti-AIDS Drug Pricing," May 29, 2007
• "U.S. Trade Policy Becoming Less Pharma-Friendly," May 18, 2007
• "The "Unfairness" of World Intellectual Property Protection According to The New Yorker," May 17, 2007
• "Worldwide Drug Pricing Regime in Chaos," May 9, 2007
• "Not Getting It about Patented Drug Prices at The Wall Street Journal," May 6, 2007
• "A Modest Proposal Regarding Drug Pricing in Developing Countries," May 2, 2007
• "The Law of Unintended Consequences Arises in Applying TRIPS to Patented Drug Protection in Developing Countries," May 1, 2007
• "Abbott Agrees to Offer AIDS Drug at Reduced Price," April 12, 2007
• "No New Abbott Medicines for Thailand," March 14, 2007
• "More Compulsory Licensing in Thailand," February 1, 2007

(Finally) It May Be Time to Stop the Hypocrisy over Stem Cell Patents

    By Kevin E. Noonan --

The U.S. Patent and Trademark Office rendered its final decision on Monday in one of the re-examinations of the Thomson stem cell patents provoked by two groups:  the Public Patent Foundation (PUBPAT), headed by Dan Ravicher, and The Foundation for Taxpayer and Consumer Rights (FTCR), a California taxpayer group.  The Patent Office decision comes in the inter partes (35 U.S.C. § 311-318) re-examination of U.S. Patent No. 7,029,913.

The inter partes requesters had asserted four grounds of unpatentability against the claims of the '913 patent:

• That the claims are unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Robertson '83 reference (Cold Spring Harbor 10: 647-63) in view of the Loring Declaration (see "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part I").
• That the claims are unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Piedrahita 1990 reference (Theriogenology 34: 879-901) in view of the Loring Declaration.
• That the claims are unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the Robertson '83 reference, the Robertson '87 reference (Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, IRL Press) and the Piedrahita 1990 reference in view of the Loring Declaration.

As set forth in the decision, the Examiner refused to adopt any of these grounds of unpatentability, since they improperly relied on the Loring declaration (which does not properly form a basis for re-examination).  The Examiner instead raised the following grounds of unpatentability:

• That the claims were unpatentable under 35 U.S.C. § 102(b) for being anticipated by U.S. Patent No. 5,166,065 to Williams, either alone or based on evidence of inherency.
• That the claims were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the '065 patent, either alone or based on evidence of inherency.
• That the claims were unpatentable under 35 U.S.C. § 102(b) for being anticipated by U.S. Patent No. 5,690,926 to Hogan, either alone or based on evidence of inherency.
• That the claims were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of the '926 patent, either alone or based on evidence of inherency.
• That the claims were unpatentable under 35 U.S.C. § 103(a) for being obvious in light of Robertson '83 reference, the Robertson '87 reference, the '065 patent, and the '926 patent.

However, in Monday's decision, the Examiner withdrew all these grounds of rejection, finding that the claims were patentable over the combinations of the cited references and under 35 U.S.C. §§ 102 and 103.  The Examiner did not merely withdraw these rejections, however, but rather set forth the basis for these determinations for all of the art and all of the arguments raised by the requestor.  Specifically, the Examiner made these determinations:

U.S. Patent No. 5,166,056 to Williams does not anticipate the '913 patent claims; the Williams patent disclosed only mouse ES cells and did not inherently enable the human ES cells claimed in the '913 patent.  Moreover, any implied teaching with regard to human ES cells was contradicted by a later paper (Cherny, 1994, Reprod. Fert. Develop. 6: 569-75; Williams co-authored), stating that isolation of human pluripotent ES cells had "remained elusive."  Moreover, the Examiner considered the "precise impetus" for Cherny, 1994 was to find alternative methods for producing ES cells from non-mouse species, because the methods used for mouse ES cells had not been "applicable to other domestic animals."  Indeed, the Examiner agreed with WARF's position that Cherny, 1994 contradicted any interpretation that the Williams patent enabled human ES cell preparation.  Finally, the Examiner believed that undue experimentation would be required to practice the methods of the Williams patent to produce human ES cells, since there could be no reasonable expectation of success in view of all of the evidence of record.

This belief was supported by evidence from the art, specifically the Gardener and Brook reference (1997, Proc. Natl. Acad. Sci. U.S.A. 94: 5709-12) and the Brook et al. reference (2003, Diabetes 52: 205-08), of the failure of others to produce human ES cells using prior art methods such as those set forth in the Williams patent.  The Examiner's undue experimentation determination was also supported by the Iannacone et al. (1994, Develop. Biol. 163: 288-92) and Ouhibi et al. (1995, Molec. Reprod. Devel. 40: 311-24) references, showing the unpredictability of producing rat ES cells.  On the other hand, Doetschman (1988, Develop. Biol. 127: 224-27) isolated hamster ES cells, but Piedrahita (1990, Theriogenology 34: 879-901) failed to isolate ES cells from pigs or sheep, and while unable to determine whether Talbot (1995, Molec. Reprod. & Develop. 42: 35-52) isolated bovine ES cells, the evidence supported the Examiner's position that the art evidence showed that ES cells were sufficiently unpredictable to amount to undue experimentation absent evidence that ES cells from a particular species had in fact been made.

The most directly applicable reference to the human ES cells of the '913 patent was the Bongso reference (1994, Human Reprod. 9: 2010-17) (see "WARF Responds to the Patent Office on Its Re-examined Stem Cell Patents").  However, although the Examiner believed that Bongso may have in fact isolated human ES cells, he was unable to maintain them in culture as recited in the claims.

With regard to obviousness under 35 U.S.C. § 103(a), the Examiner determined that the Williams patent did not support a prima facie obviousness determination, expressly considering the matter under the Supreme Court's recent KSR Int'l Co. v Teleflex Inc. decision.  Specifically, the Examiner determined that the art failed to provide a reasonable expectation of success in achieving the claimed invention, in view of the previously-determined unpredictability in producing ES cells from a variety of mammalian species (including human).  The Examiner also determined that evidence of "public acclaim" submitted by WARF would be properly considered as one of the "secondary indicia" of non-obviousness if WARF had established the source of the acclaim as being from those of at least ordinary skill in the art.  Since the Examiner concluded that the evidence did not support a prima facie obviousness determination, he did not need to consider the secondary indicia in this case.

Importantly, the Examiner also determined that the declaration evidence submitted by the third party requestor to the effect that Dr. Thomson succeeded in isolating human ES cells where others failed merely due to access to resources (human embryos) and funding others did not have, was merely hindsight reasoning and thus impermissible for consideration in an obviousness determination.  The Examiner also noted for the record that at least two of the declarants were not disinterested parties.

Turning to the Hogan patent, the Examiner determined that the EG cells disclosed by Hogan are distinct from the ES cells claimed in the '913 patent, and thus that the Hogan patent neither anticipates nor renders obvious the claims of the '913 patent.  The Examiner's conclusions were based on comparisons between characteristic properties of the two cell types, including the presence or absence of certain cell surface markers (such as SSEA-1).

Finally, the Examiner considered whether the combination of the '065 patent and the '926 patent, in view of the Robertson '83 reference or the Robertson '87 reference rendered obvious the invention claimed in the '913 patent.  He found that while the two Robertson references disclosing mouse ES cells provided strong motivation in the art to produce human ES cells, the unpredictability in the art noted above made the claimed invention non-obvious.  The Examiner came to the same conclusion with regard to the combination of the '065 patent and the '926 patent with the Piedrahita 1990 reference discussed above.  The Examiner came to the same conclusions when considering the obviousness question in view of the teachings of all these references combined.

The Patent Office decision issued Monday was not a Notice of Allowance or other final determination.  Rather, it was a (non-final) Action Closing Prosecution.  According to the paper itself, no appeal could be taken from this Action; the patentee has one month to file a "submission," and if one is filed the Third Party Requester has the right to file responsive comments within 30 days.  Thereafter, the Office will issue a Right of Appeal Notice pursuant to 37 C.F.R. § 1.953(a), giving the parties one month to file an appeal to the Board of Patent Appeals and Interferences.

One final note:  the patentee submitted amendments to the claims that the Examiner states are not necessary for patentability but that "provide further clarity to the claims."  Presumably, a re-examination certificate will include the amendments to the claims, which are as follows:

1.  A replicating in vitro cell culture of pluripotent human embryonic stem cells derived from a pre-implantation embryo, the culture comprising cells which (i) [[are capable of proliferation]] will proliferate in an undifferentiated state in in vitro culture for over one year without the application of exogenous leukemia inhibitory factor, (ii) maintain a karyotype in which the chromosomes are euploid through prolonged culture, (iii) maintain the potential to differentiate to derivatives of endoderm, mesoderm, and ectoderm tissues throughout the culture, and (iv) are inhibited from differentiation when cultured on a fibroblast feeder layer.

2.  The in vitro cell culture [[preparation]] of claim 1, wherein the stem cells will spontaneously differentiate to trophoblast and produce chorionic gonadotropin when cultured to high density.

3.  The in vitro cell culture [[preparation]] of claim 1 wherein the cells are negative for the SSEA-1 marker, positive for the SSEA-4 marker, and express alkaline phosphatase.

Two ex parte re-examinations (35 U.S.C. § 302-307) remain:  Control No. 90/008102 for U.S. Patent No. 5,843,780 (claiming primate embryonic stem (pES) cells) and Control No. 90/008139 for U.S. Patent No. 6,200,806 (claiming human embryonic stem cell (hES) cells).  Since the progress of these re-examinations have paralleled the inter partes re-examination, and in view of the "special dispatch" provisions of the re-examination rules, we should expect a decision in these re-examinations shortly.

For information regarding this and other related topics, please see:

• "WARF Licenses Stem Cell Patent Portfolio to BioTime," January 23, 2008
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part III," July 4, 2007
• "WARF Responds to the Patent Office on Its Re-examined Stem Cell Patents," June 26, 2007
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part II," April 26, 2007
• "It's Time to Stop the Hypocrisy over Stem Cell Patents - Part I," April 17, 2007
• "WARF Stem Cell Patent Claims Rejected in Re-examination," April 3, 2007

Finally, Some Good News for Genentech on Avastin®

    By Kevin E. Noonan --

It has been a difficult year for Genentech with regard to its blockbuster anticancer drug, Avastin® (bevacizumab).  For much of the year, the company was embroiled in a dispute with the ophthalmological community over its decision (now altered) to limit sale of Avastin® for reformulation in treating age-related macular degeneration (AMD) in favor of Lucentis®, a related (and much more expensive) formulation of a Fab fragment of the same monoclonal antibody drug but having the advantage of FDA approval for AMD treatment (see links below).  Then, just last December, the FDA's Oncology Drug Advisory Committee voted 5-4 to recommend Avastin® not be approved for treating metastatic breast cancer.  The basis for the decision was the absence of a clinical trial of 722 women with metastatic breast cancer, where patients receiving a combination of Avastin® and paclitaxel showed lack of tumor growth for 11.8 months, compared with 5.8 months in patients receiving paclitaxel alone.  However, there was no improvement in overall survival (26.5 months versus 24.8 months), and patients receiving Avastin® suffered significant side effects, including high blood pressure, blood clots, heart problems, bowel perforation, and evidence of kidney damage.  These results were in contrast with results obtained for Avastin® treatment for lung and colon cancer, where significant overall survival times were improved.  They were, however, consistent with an earlier study showing no improved survival times for breast cancer patients treated with the combination of Avastin® and another anticancer drug, capecitabine.

On Friday, the FDA took the unusual step of rejecting the Advisory Panel's recommendation and approving Avastin® for breast cancer treatment in combination with other anticancer drugs like paclitaxel.  Moreover, it granted accelerated approval to this indication of the drug, which is intended "to make promising products for life-threatening diseases available on the market on the basis of preliminary evidence prior to formal demonstration of patient benefit," according to the FDA's website.  Approval is important, as it is estimated to increase Genentech's already healthy Avastin® sales figures ($2.3 billion in 2007) by almost half a million dollars per year.  FDA approval triggers both insurance reimbursement for the treatment and a commitment from Genentech that the cost of treatment will be capped at $55,000 per year (it can cost as much as $100,000 per year without the cap).  It is also expected to increase the number of metastatic breast cancer patients getting Avastin® combination therapy from the approximately 9,500 patients currently getting "off-label" treatment.

The decision raises questions of how the FDA will address approval standards for late-stage cancer treatments.  According to Dr. Kay Dickerson of the Center for Clinical Trials at Johns Hopkins University, "[i]f FDA sets a precedent of approving a drug based on progression free survival, people are afraid they may stop looking at survival as the most important endpoint."  The decision also suggests an acceptance at the FDA of principles advocated by academic critics (and supporters) of the FDA, such as Professor Richard Epstein at the University of Chicago Law School (see "Overdose: How Excessive Government Regulation Stifles Pharmaceutical Innovation"), that the FDA should permit patients to make the judgment of whether to use drugs like Avastin® for terminal diseases.  However, those espousing such "free market" solutions neglect to consider whether decisions like the FDA's approval of Avastin® represents an abdication of the agency's responsibility to make scientifically-reasoned, dispassionate assessments of drug efficacy for individuals in the throes of deadly diseases, whose capacity for dispassion may be compromised.  While certainly the case that the drug can give patients hope (a sentiment expressed by Margaret C. Kirk, Executive Director of the Y-ME National Breast Cancer Organization), whether this is enough to determine approval as a consistent policy is an important question the FDA has yet to adequately address.

For additional information regarding this and other related topics, please see:

• "Compromise Resolves Avastin® Dispute," December 26, 2007
• "Genentech Beset with Avastin® Woes," December 6, 2007
• "Age-related Macular Degeneration Patients Get a (Limited) Reprieve," November 7, 2007
• "Genentech Acts to Halt Off-label Use of Avastin® for Age-related Macular Degeneration," October 21, 2007
• "Genentech CEO Defends Differential Cost for Avastin®/Lucentis® Treatment of Macular Degeneration," June 6, 2007
• "Retinal Specialist on the Avastin®/Lucentis® Controversy," February 23, 2007
• "Lower Doses of Genentech's Avastin® Effective in Treating Lung Cancer," February 23, 2007

BIO CEO Provides Update on Patent Reform and Follow-on Biologics Legislation - Part II

    By Donald Zuhn --

Earlier today, Patent Docs participated in a conference call with Jim Greenwood (at right), the President and CEO of the Biotechnology Industry Organization (BIO).  Mr. Greenwood, who represented Pennsylvania's Eighth District in the U.S. House of Representatives from January 1993 through January 2005 prior to his BIO appointment, had invited the press and a handful of biotech and pharma bloggers to participate in the conference call, where he provided a briefing on the prospects for passage of biologics legislation and patent reform legislation in this Congress.  Mr. Greenwood expressed the hope, in view of the time and effort expended in "educating" legislators to the intricacies of these issues, that progress can be made with respect to both pieces of legislation in order to avoid having to retrace steps were the legislation left to the next Congress and administration.

With respect to follow-on biologics, Mr. Greenwood quickly dispelled any notion that BIO or its membership stood in opposition to the passage of follow-on biologics legislation, stating that "Congress ought to act," and noting that BIO had been actively encouraging both houses of Congress to report a bill.  Mr. Greenwood contended that securing passage of a suitable follow-on biologics bill was important because biologics innovators could have difficulty fending off generics with just their patents alone, which might provide no protection, or only weak protection, against biosimilars.  According to Mr. Greenwood, BIO found H.R. 1956, which was introduced by Rep. Jay Inslee (D-WA; at left) last April, to be an acceptable bill.  Mr. Greenwood noted that another potentially suitable bill could soon be introduced by Rep. Anna Eshoo (D-CA; at right).  Rep. Eshoo's bill, which is said to be a compromise between "generics-friendly" legislation written by Rep. Henry Waxman (D-CA) and Rep. Inslee's "brand-friendly" legislation, recently picked up the support of Rep. Joe Barton (R-TX), the top Republican on the House Energy & Commerce Committee (see "Barton Backs Eshoo's Biosimilars Plan").

Whichever bill BIO ultimately backs, Mr. Greenwood stressed the importance of striking a fair balance between the demands of the brand names and those of the generics, stating that "if you give companies incentives to create new drugs, they will."  Mr. Greenwood acknowledged that the sticking point with regard to passage of follow-on biologics legislation would continue to be the period of data exclusivity.  When asked whether BIO would be satisfied with splitting the difference between a 12-year exclusivity period backed by the generics industry and the 14-year period of Rep. Inslee's bill, Mr. Greenwood expressed skepticism that generics would support a 12-year period, stating that "if the generics were at 12, we would have a Valentine's Day love fest."

In addition to providing Mr. Greenwood with an opportunity to once again address patent reform and follow-on biologics legislation (Patent Docs readers will recall that Mr. Greenwood had addressed both topics in a conference call last September; see "BIO CEO Provides Briefing on Follow-On Biologics and Patent Reform"), the session with the media also provided BIO with an opportunity to present a number of its position papers on the topics.  In a paper entitled "BIO Principles on Follow-On Biologics," the organization outlined principles that Congress should recognize when crafting a follow-on biologics bill.  Among the key principles that BIO lists are the following:

• Ensure patient safety by mandating that follow-on biologics approval be based on the same rigorous standards of safety, purity, and potency that are applied by Food and Drug Administration (FDA) to the approval of innovator drugs, and assigning follow-on biologics a non-proprietary name that is readily distinguishable from that of the innovator drug.

• Because biologics are more complex than small molecule drugs, follow-on biologics legislation should recognize the scientific differences between the two classes of molecules.  For example, small manufacturing differences between a follow-on biologic and innovator drug can, in contrast with small molecule drugs, result in significant safety or effectiveness differences.

• Preserve incentives for innovation by providing "substantial" non-patent data exclusivity, during which time follow-on biologics manufacturers could not rely on the FDA's prior approval of innovator biologics to support approval of the follow-on manufacturer's own products.  According to the BIO position paper, such data exclusivity is necessary because of the biologics industry's "heavy dependence on access to significant amounts of high-cost public and private investment capital, and the high risks and costs involved in the development of new biologic medicines."

In a companion piece to this article, Kevin Noonan discussed Mr. Greenwood's comments on patent reform legislation.

For additional information on this and other related topics, please see

• "Insmed Announces National Awareness Campaign Regarding Follow-on Biologics," February 13, 2008
• "Millennium Pharmaceuticals Spent $1.28 Million on Lobbying in 2007," February 8, 2008
• "Biologics Legislation Faces Unresolved Issues," December 28, 2007
• "BIO CEO Provides Briefing on Follow-On Biologics and Patent Reform," September 18, 2007
• "Biotechs Facing New Challenges," August 13, 2007
• "Three New Biosimilars Pass EMEA Test," July 26, 2007
• "European Medicines Agency Releases Paper on Biosmiliar Medicines," July 23, 2007
• "Senate Committee Passes Biologics Legislation," July 5, 2007

BIO CEO Provides Update on Patent Reform and Follow-on Biologics Legislation - Part I

    By Kevin E. Noonan --

Earlier today, Patent Docs participated in a conference call with Jim Greenwood (at right), the President and CEO of the Biotechnology Industry Organization (BIO).  Mr. Greenwood, who represented Pennsylvania's Eighth District in the U.S. House of Representatives from January 1993 through January 2005 prior to his BIO appointment, had invited the press and a handful of biotech and pharma bloggers to participate in the conference call, where he provided a briefing on the prospects for passage of biologics legislation and patent reform legislation in this Congress.  Mr. Greenwood expressed the hope, in view of the time and effort expended in "educating" legislators to the intricacies of these issues, that progress can be made  with respect to both pieces of legislation in order to avoid starting over were the legislation left to the next Congress and administration.

The costs of these additional efforts are not worth passage of pending legislation, however, especially with regard to the patent "reform" bill under consideration by the Senate.  Indeed, BIO's position on the Senate patent reform bill is that "no bill is better than this bill," and Mr. Greenwood vowed that BIO would continue to vigorously oppose the pending bill and to work to prevent cloture of debate and a vote, something Senators Leahy (D-VT) and Hatch (R-UT) have promised to do in this session.

BIO agrees with several portions of the bill, including the venue provisions and establishment of some form of post-grant review along the lines of European oppositions which must be filed within nine months of patent grant.  However, it opposes unlimited opportunities to challenge patents (the so-called "second window") for oppositions; citing an economic analysis by Robert J. Shapiro and Aparna Mathur (see "The Economic Implications of Patent Reform: The Deficiencies and Costs of Proposals Regarding the Apportionment of Damages, Post-Grant Opposition, and Inequitable Conduct"), permitting an unlimited opposition period would increase the costs of the system 100-fold, to 1.6 billion dollars a year.  BIO also believes the inequitable conduct provisions of the bill are "nonsensical."  Of particular concern are the apportionment of damages provisions, which BIO argues would encourage patent infringers to consider infringement damages as just another "cost of doing business" and thus devalue patents to the detriment of investment.  On this issue, BIO believes the patent reform process was "hijacked" by the information technology and financial industries, which used intensive lobbying and fundraising efforts to encourage the current provisions of the bill.  Mr. Greenwood thinks the tide may be turning on this point, however, in view of opposition from the Bush administration, BIO and other industry groups, and letters from Senate constituents, including ones from the Association of American Universities, and a number of trade unions (see links below).  However, Mr. Greenwood also acknowledged that patent legislation "puts Members of Congress to sleep" and that made progress in getting a good bill an uphill battle.  A result of the polarized opinions and consequences of the damages provisions of the bill on different industries is that voting on the bill would put Senators in the uncomfortable position of favoring one portion of their constituencies over another, which they would rather not do.  Another consequence of this disparate impact is that it implicates provisions of the TRIPS agreements that mandate there be no disproportionate treatment of different types of intellectual property, but Mr. Greenwood made it clear that he was not contending that passage of the Senate bill would constitute a TRIPS violation.

Finally, since Mr. Greenwood expects that the various stakeholders will get about a week's notice before the bill comes to the Senate floor, as well as disclosure of any amendments Senators Leahy or Hatch intend to report with the bill, the likelihood of a vote in February is diminishing.  In response to a question, Mr. Greenwood said our information was as good as his as to when the bill might come to the Senate floor for a vote.

[NOTE:  As reported by the Intellectual Property Owners Association (IPO) this morning, Senator Leahy (at right) told Congressional Quarterly Today that the bill won’t come to a vote until after the two-week March recess that ends March 28th, and that "certain sections" will be subject to redrafting.]

In a companion piece to this article, Donald Zuhn will be discussing Mr. Greenwood's comments on the follow-on biologics legislation.

For additional information on this and other related topics, please see:

• "BIO Report Indicts "Patent Reform" Proponents," February 13, 2008
• "Millennium Pharmaceuticals Spent $1.28 Million on Lobbying in 2007," February 8, 2008
• "Patent Reform and Infringement Damages: Some Economic Reasoning," February 5, 2008
• "Department of Commerce Sends Letter on Patent Reform to Senator Leahy," February 4, 2008
• "Biotech and Pharma Opposition to Senate Patent Reform Bill," February 3, 2008
• "The Letters Keep Coming Over the Senate Transom," January 30, 2008
• "U.S. Senate Mailbox Filling with Letters against Passage of Patent 'Reform' Bill: An Update," January 23, 2008
• "U.S. Senate Mailbox Filling with Letters against Passage of Patent 'Reform' Bill," January 18, 2008
• "Patent Reform Discussed on Senate Floor," December 21, 2007
• "Enjoined New Rules and Patent Reform Finally Appearing on Biotech Industry's Radar," December 20, 2007
• "Chinese IP Judge Discusses Implications of U.S. Patent Reform Bill and Two Congressmen Heed Warning," December 17, 2007
• "IPO President Seeks Deletion of Patent Reform Provision," December 12, 2007
• "Senate May Act on Patent 'Reform' Bill in the New Year," December 2, 2007
• "The Wall Street Journal Gets It Half Right," November 5, 2007
• "BIO CEO Provides Briefing on Follow-On Biologics and Patent Reform," September 18, 2007
• "Patent 'Reform' Bill Passes House of Representatives," September 9, 2007
• "Reversal in Microsoft Case Weakens Patent Reform Argument," August 7, 2007
• "San Francisco Chronicle Opines on Patent Reform," August 6, 2007
• "Patent Reform Bill to Be Delayed?" June 12, 2007
• "Senate Judiciary Committee Holds Hearing on Patent Reform," June 10, 2007
• "Could Creating a U.S. 'Utility Model' Patent Fulfill the 'Need' for Patent Law Reform?" May 21, 2007