Thursday, April 05, 2007

"The Deal" gets the WARF patent re-exam wrong

Alex Lash wrote in The Deal of the initial Office Action in the re-exam of the WARF patents:

In a decision that could widen the field for embryonic stem cell research in the U.S., the government's patent office has overturned 10-year-old patents held by the University of Wisconsin after a complaint brought by two watchdog groups.

IPBiz notes that the first (non-final) Office Actions in this case did NOT overturn any patents. The WARF patents are still in force.

Lash also wrote:

A challenge to the patents brought last summer by the Public Patent Foundation and the Foundation for Taxpayer and Consumer Rights convinced the patent examiner that researchers in the U.S. and Australia had done work before Thomson with embryonic stem cells from humans and other mammals that made the WARF claims "obvious" -- patent language for not innovative enough.

IPBiz notes that Williams (Australia) did not do ANY work with embryonic stem cells from humans in US 5,166,065. What Hogan (U.S.) did is reported below. One does not find isolation or maintenance of human stem cells done by Hogan in US 5,690,926. Thus, the idea of "work before Thomson with embryonic stem cells from humans" is not correct as to the '065 and '926 patents.

Lash is flat-out wrong when he writes: It's possible the examiner could reverse course and reinstate the patents. The patents are in force RIGHT NOW, and don't need to be reinstated. The examiner could withdraw the rejection, at which point the examiner could direct the issuance of a re-exam certificate (claims stay the same) OR the examiner could make new rejections (recall the Eolas/Berkeley case).

Lash misses the point when he writes: WARF cannot argue it didn't know about earlier work, so it must frame Thomson's work as a great leap. WARF has to show that its claims are novel and nonobvious, which is a different matter from "great leap." Lash neglects to point out that Thomson cited prior art MORE pertinent than what is being brought up now. Citations include Bongso, et al., "Isolation and culture of inner cell mass cells from human blastocysts", Human Reproduction, 9:2110-2117, 1994. Brown, et al., "Criteria that optimize the potential of murine embryonic stem cells for in vitro and in vivo developmental studies", In Vitro Cell. Dev. Biol. 284:773-778, Dec. 1992. Damjanov, et al., "Retinoic acid-induced differentiation of the developmentally pluripotent human germ cell tumor-dervied cell line, NCCIT", Laboratory Investigation, 68:220-232, 1993. Nation/World, "Embryonic monkey cells isolated". -Nov. 4, 1994. Bongso, A., et al., "The Growth of Inner Cell Mass Cells from Human Blastocysts," Theriogenology, 41:167 (1994).

In contrast the most recent journal cited in the Hogan patent is from 1992: e.g., Matsui et al., Cell 70:841-847 (1992). The Hogan patent cites one paper by Piedrahita et al.: Theriogenology 29:286 (Jan. 1988), but does NOT cite the 1990 Piedrahita paper cited against the WARF patents. Significantly, the Hogan patent does cite Williams, US 5166065; if Hogan was patented over Williams, one wonders how the USPTO can reject Thomson over Williams. [The application filing date for Hogan is March 25, 1994.]

In US 5,690,926, Brigid L. M. Hogan of Vanderbilt had a claim 6 which stated:

An isolated human pluripotential cell wherein said cell exhibits the following characteristics:

(a) can be maintained on feeder layers for at least 20 passages; and

(b) gives rise to embryoid bodies and differentiated cells of multiple phenotypes in monolayer culture; and wherein said cell is derived from a human primordial germ cell by the process of:

(1) culturing a human primordial germ cell in a composition comprising basic fibroblast growth factor, leukemia inhibitory factor, membrane associated steel factor, and soluble steel factor;

(2) selecting cells that have characteristics (a) and (b), above, and

(3) isolating said human pluripotential cell.

This claim finds support in the specification at column 2, lines 29-34.

Column 5, lines 1-4 mentions this invention provides a non-mouse pluripotential ES cell...

Elswhere in the specification, one has the text:

This invention provides a non-mouse pluripotential ES cell which can be maintained on feeder layers for at least 20 passages, and give rise to embryoid bodies and multiple differentiated cell phenotypes in monolayer culture. Only those non-mouse animals which can be induced to form ES cells by the described methods are within the scope of the invention. Given the methods described herein, an ES cell can be made for any animal. However, mammals are preferred since many beneficial uses of mammalian ES cells exist. Mammalian ES cells such as those from rats, rabbits, guinea pigs, goats, pigs, cows, and humans can be obtained. Alternatively, embryos from these animals can be screened for the ability to produce ES cells.

But what was actually done? An important part of the specification is in the following. IPBiz alerts readers to verb tenses, which are significant in the patent business. The use of "past tense" denotes something that was, in fact, done. The use of the "present tense" does not.

From the specification:

Method for the isolation of pluripotential stem cells from human primordial germ cells and human embryonic (fetal) gonads

The above methods for isolation of ES cells from murine embryos were repeated for isolation of ES cells from human embryos. Specifically, testes were dissected from a 10.5 week human embryo. Younger or older embryos represent alternative sources. The preferred age range is between 8.5 weeks and 22 weeks. Tissue was rinsed in buffered saline, and incubated in trypsin solution (0.25% trypsin, 1 mM EDTA in Ca.sup.30 + /Mg.sup.++ free HEPES buffered saline) for 10 minutes at C. The tissue was dissociated by pipetting and the cells plated into wells of a 24 well tray containing irradiated feeder cells. In this experiment the feeder cells were Sl/Sl mouse fibroblasts transfected with human membrane associated Stem Cell Factor (Sl.sup.4 h220 cells from Dr. David Williams, HHMI, Indiana State University School of Medicine). An alternative feeder layer would consist of a mixture of mouse or human embryo fibroblasts and Sl.sup.4h220 cells, to provide a more coherent layer for long term cell attachment. The culture medium consists of Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum supplemented with 10 ng/ml human bFGF, 60 ng/ml human Stem Cell Factor and 10 ng/ml human LIF. Alternatively, the amounts of bFGF can be increased (e.g. 20 ng/ml). Other alternative or additional supplements can be added at this time, for example IF-6, IL-11, CNTF, NGF, IGFII, flt3/flk2 ligand, and/or members of the Bone Morphogenetic Protein family. The cultures were maintained for 5 days, with daily addition of fresh growth factors. Longer culture could also be utilized, e.g. 5 to 20 days.

After 10 days the cultures were fixed and stained for alkaline phosphatase activity. Colonies of cells expressing high levels of alkaline phosphatase and closely resembling primordial germ cells of the mouse embryo were detected in many wells (see FIG. 5). Closely packed clusters of cells were present in some colonies (arrow in FIG. 5). In cultures of mouse embryo germ cells these colonies give rise to lines of pluripotential embryonic stem cells. Therefore, the identified human cells can give rise to cell lines.

IPBiz notes the change to the "present tense" rather than the "past tense" in the verbs in the last two sentences. The present tense is used when one is being prophetic ("I can do something") as distinct from the past tense ("I did do something").

Similarly, note the use of the present tense in the following:

Testes are dissected and the tunica removed. The testes are then incubated at C. with mild shaking in buffered saline containing bovine serum albumin and collagenase (final concentration approximately 0.5 mg/ml). When the tissue has dissociated the tubules are allowed to settle out and then washed in saline several times. The collagenase treatment is repeated to remove all the cells surrounding the tubules (Leydig cells and connective tissue). The tubules are then washed and treated with hyaluronidase in buffered saline (final concentration approximately 0.5 mg/ml) at C. until the tubules are free of adherent material. The tubules are washed and placed onto tissue culture dishes coated with Poly-L-lysine. The Sertoli cells attach strongly to the dish and spread out, while the germ cells remain in suspension. The germ cells are collected and plated onto a layer of irradiated feeder cells comprising membrane bound and soluble stem cell factor, LIF and basic FGF as described above.

Note also the text: The preceding examples are intended to illustrate but not limit the invention. While they are typical of those that might be used, other procedures known to those skilled in the art may be alternatively employed.

WARF will have the burden of showing Hogan is NOT enabled as to stem cells (isolation and maintenance) and/or that the product/method of Hogan is not within the scope of WARF claims.

An earlier discussion of the first Office Action in the re-exam of the '780 patent can be found:


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