Source: https://www.patentdocs.org/2008/03/yes-it-is-time.html
Timestamp: 2020-03-31 23:55:50
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Patent Docs: Yes, It IS Time (Finally) to Stop the Hypocrisy over Human Stem Cell Patents
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Yes, It IS Time (Finally) to Stop the Hypocrisy over Human Stem Cell Patents
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:
(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:
(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
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 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;
(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.
12. A method of isolating a pluripotent human embryonic stem cell line, the method comprising the steps of:
(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.
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?
• "(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
Posted at 11:46 PM in Biotech/Pharma News, Patent Prosecution | Permalink