Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`
`
`
` Paper No. 46
`
` Entered: November 28, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`OSI PHARMACEUTICALS, LLC
`and GENENTECH, INC.,
`
`Petitioner,
`v.
`ARCH DEVELOPMENT CORP. and
`DANA-FARBER CANCER INSTITUTE, INC.,
`
`Patent Owner.
`____________
`
`Case IPR2016-01034
`Patent 7,838,512 B1
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Request for Rehearing
`37 C.F.R. §42.71
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
`
`
` Paper No. 46
`
` Entered: November 28, 2017
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`OSI PHARMACEUTICALS, LLC
`and GENENTECH, INC.,
`
`Petitioner,
`v.
`ARCH DEVELOPMENT CORP. and
`DANA-FARBER CANCER INSTITUTE, INC.,
`
`Patent Owner.
`____________
`
`Case IPR2016-01034
`Patent 7,838,512 B1
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Request for Rehearing
`37 C.F.R. §42.71
`
`
`
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`
` INTRODUCTION
`
`A.
`
`Background
`In our Final Written Decision (Paper 43, “Dec.”), we held that claims
`1–3, 5, and 6 (collectively, “the challenged claims”) of U.S. Patent
`No. 7,838,512 B1 (Ex. 1001, “the ’512 patent”) were unpatentable over
`Akinaga,1 in view of the knowledge of a person of ordinary skill in the art,
`Seynaeve,2 Friedman,3 and Tam4 (Ground IV). See Dec. 38–39.5 Patent
`Owner timely filed a Request for Rehearing requesting that we vacate the
`portion of our Decision relating to that Ground. Paper 44 (“Reh’g Req.”).6
`We did not authorize any response to the Request for Rehearing.
`For the reasons that follow, we deny Patent Owner’s Request for
`Rehearing.
`
`
`1 Shiro Akinaga et al., Enhancement of Antitumor Activity of Mitomycin C In
`Vitro and In Vivo by UCN-01, a Selective Inhibitor of Protein Kinase C, 32
`CANCER CHEMOTHERAPY AND PHARMACOLOGY 183–89 (1993). Ex. 1004.
`2 Caroline M. Seynaeve et al., Cell Cycle Arrest and Growth Inhibition by
`the Protein Kinase Antagonist UCN-01 in Human Breast Carcinoma Cells,
`53 CANCER RES. 2081–86 (1993). Ex. 1014.
`3 BethAnn Friedman et al., Regulation of the Epidermal Growth Factor
`Receptor by Growth-Modulating Agents: Effects of Staurosporine, a Protein
`Kinase Inhibitor, 50 CANCER RES. 533–38 (1990). Ex. 1031.
`4 Sun W. Tam and Robert Schlegel, Staurosporine Overrides Checkpoints
`for Mitotic Onset in BHK Cells, 3 CELL GROWTH & DIFFERENTIATION 811–
`17 (1992). Ex. 1012.
`5 We note that Paper 43, the Final Written Decision, issued September 11,
`2017, contains font changes introduced during the uploading process. Paper
`43 is hereby republished to eliminate the unintended font changes.
`6 We further found claim 6 invalid for reasons not at issue here.
`2
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`Standard for Reconsideration
`B.
`The applicable standard for a request for rehearing is set forth in
`37 C.F.R. § 42.71(d), which provides in relevant part:
`A party dissatisfied with a decision may file a request for
`rehearing, without prior authorization from the Board. The
`burden of showing a decision should be modified lies with the
`party challenging the decision. The request must specifically
`identify all matters the party believes the Board misapprehended
`or overlooked, and the place where each matter was previously
`addressed in a motion, an opposition, or a reply.
` ANALYSIS
`
`Patent Owner argues that we should grant its Request for Rehearing
`because our conclusion is based on findings that 1) staurosporine was
`known to inhibit the tyrosine kinase c-src in human and animal cells; and 2)
`that staurosporine has a structure and mechanism of action similar to UCN-
`01, such that one of ordinary skill in the art would expect UCN-01 to
`likewise inhibit tyrosine kinases such as c-src. See Reh’g Req. 1–2. As an
`initial matter, we reject the premise of Patent Owner’s argument that our
`Decision stands or falls on whether one of ordinary skill in the art would
`have understood that UCN-01 inhibits the tyrosine kinase c-src in human
`and animal cells.
`As illustrated in claim 1, the challenged claims are generally directed
`to administering a chemotherapeutic DNA damaging agent in combination
`with a low molecular weight tyrosine kinase inhibitor.7 According to the
`Specification, this combination is beneficial because treatment with a DNA
`damaging agent promotes cell cycle arrest, during which time cells attempt
`
`7 Patent Owner concedes that claim 1 is representative and does not argue
`claims 2, 3, 5, and 6 separately. See, e.g., PO Resp. 3.
`3
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`to repair DNA damage before undergoing mitosis and subsequent cell
`division. See Dec. 4–6. Tyrosine kinase inhibitors, however, force cells to
`override the cell cycle arrest checkpoint and enter mitosis before repairs are
`complete, thereby enhancing the cytotoxic effects of the DNA damaging
`agents. Id.
`As discussed in our Decision, Akinaga examines the effect of
`UCN-01 alone, and in combination with the DNA damaging agent
`mitomycin C. See Dec. 27–28; Ex. 1004. Noting that the two compounds
`had 1) complementary effects in delaying cell cycle progression; and 2)
`synergistic cytotoxic and antitumor effects, Akinaga expressly suggests the
`combination of UCN-01 and DNA-damaging agents for cancer
`chemotherapy. Id. Seynaeve establishes that UCN-01 inhibits multiple
`tyrosine kinases in human breast cancer cells coincident with promoting
`cell cycle arrest. Dec. 28–29, 34–35; Ex. 1014. Accordingly, “Seynaeve
`proposes a link between UCN-01’s inhibitory effects on tyrosine kinases
`and its inhibitory effects on the cell cycle.” Dec. 29.8
`Akinaga further suggests combining a chemotherapeutic DNA
`damaging agent with UCN-01 because the two compounds cause delays in
`different stages of the cell cycle and result in synergistic cytotoxic and
`antitumor effects, whereas Seynaeve examines the effects of UCN-01 on
`the cell cycle of human carcinoma cells and shows that UCN-01 is a
`tyrosine kinase inhibitor. See Dec. 37–38. Because both references
`
`
`8 Considering Seynaeve teachings with respect to UCN-01, we reject Patent
`Owner’s contention that “there is no evidence from which one can
`reasonably find that Petitioner carried its burden of proving that people of
`ordinary skill in the art considered either staurosporine or UCN-01 to be
`tyrosine kinase inhibitors.” See Reh’g. Req. 6.
`4
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`investigate the effect of UCN-01 on cell cycle arrest in human tumor cells,
`one of ordinary skill in the art would have found reason to combine their
`teachings. See id.
`Accordingly, our Decision holding claims 1–3, 5, and 6 unpatentable
`under Ground IV is supported by substantial evidence irrespective of
`whether one of ordinary skill in the art would have understood that UCN-01
`inhibits c-src in human and animal cells. We, nonetheless, address the
`specifics of Patent Owner’s arguments.
`
`A.
`
`Robinson
`In our Decision, we rejected Patent Owner’s contention that although
`Akinaga teaches that UCN-01 inhibits v-src (as does Seynaeve), one of
`ordinary skill in the art would have no reason to believe that UCN-01 would
`inhibit its cellular homolog c-src because v-src is “found only in chickens”
`and “is more difficult to inhibit.” Dec. 28, 32. We instead credited the
`testimony of Petitioner’s expert, Dr. Eastman that “[b]ecause v-Src and
`c-Src have similar structures, compounds that inhibit the tyrosine kinase
`activity of v-Src generally inhibit c-Src as well. Thus, a person of ordinary
`skill would have understood that an inhibitor of v-Src would also inhibit the
`c-Src protein present in A431 cells and other human tumors.” Id. at 33
`(quoting Ex. 1002 ¶ 202). Dr. Eastman testified that Robinson, for
`example, showed “that staurosporine, a molecule very similar to UCN-01,
`inhibited both v-Src and c-Src. . . . Thus, a person of ordinary skill in the
`art would have recognized that UCN-01 would inhibit tyrosine kinases in
`both animals and humans.” Id.
`According to Robinson, “[t]he elevation in the tyrosine-specific
`kinase activity of pp60 c-src in human carcinoma . . . is suggestive that
`appropriate tyrosine kinase inhibitors may represent a new class of cancer
`5
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`therapeutics.” Ex. 1036, 256. Accordingly, Robinson screened a large
`number of compounds for tyrosine kinase inhibitory activity against
`isolated c-src protein, also known as pp60c-src. Id. at 255, Table 1.
`Consistent with Dr. Eastman’s testimony, Robinson reports that “[t]he most
`potent inhibitory effects [were] produced with staurosporine,” a “broad
`spectrum protein kinase inhibitor[].” Id. at 255, 257. Robinson emphasizes
`that, “[c]onsistent with previous reports, staurosporine was a potent
`inhibitor of pp60src.” Id. at 257.
`Robinson further reports that staurosporine inhibited the colony
`formation of activated c-src transformed cells in soft agar with “IC50 values
`. . . in the same range as IC50 values for the isolated c-src enzyme.” Id. at
`255. Robinson further determined that, although staurosporine and other
`agents inhibited colony formation of c-src transformed cells, they also
`inhibited the colony formation induced by different oncogenes “suggesting
`no selective inhibition of the src mediated transformation was being
`produced.” Id., Abstract. In view of these results, Robinson posits that:
`The lack of whole cell selectivity observed for staurosporine,
`quercetin, genistein and herbimycin A on oncogene transformed
`NIH3T3 cells perhaps reflects the multiple actions attributed to
`each of these agents. For example the broad spectrum of kinase
`inhibitory activity for staurosporine and the indication that
`protein kinase C may be more sensitive than pp60src to its
`inhibitory effects may be partially responsible for the equipotent
`effects produced on colony formation of the variety of NIH3T3
`transformants examined. Protein kinase C inhibition may also
`
`6
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`be involved with the toxicity produced before any meaningful
`antitumor activity when tested in vivo.
`Id. at 257 (internal citations omitted). Robinson concludes that “the
`compounds examined do not show appropriate whole cell effects to warrant
`development efforts.” Id. at 258.
`Patent Owner now argues that because Robinson did not consider
`staurosporine a candidate for drug development as a tyrosine kinase
`inhibitor, one of ordinary skill in the art would not understand that
`staurosporine inhibits c-src in human or animal cells. See Reh’g Req. 5–6.
`Patent Owner’s argument is unsupported by expert testimony or a plain
`reading of Robinson.
`Robinson expressly identifies staurosporine as an inhibitor of c-src
`tyrosine kinase but posits that staurosporine’s effects in cellular assays may
`be due to “multiple actions.” See Ex. 1036, 257.9 In this respect, Robinson
`raises the possibility that “protein kinase C may be more sensitive” to
`staurosporine than the tyrosine kinase c-src. Id. Contrary to Patent
`Owner’s urging, we do not equate Robinson’s failure to observe an effect
`attributable to tyrosine kinase inhibition in some assays with a conclusion
`that staurosporine is not a “low molecular weight tyrosine kinase inhibitor,”
`as required by claim 1.
`We further note that Robinson evaluates the use of tyrosine kinase
`inhibitors such as staurosporine as individual antitumor agents. That
`
`
`9 Consistent with Robinson, “Tam teaches that ‘[s]taurosporine is a potent
`general protein kinase inhibitor that can suppress in vitro the activity of
`phospholipid Ca2+-dependent and cyclic nucleotide-dependent
`serine/threonine protein kinases as well as the tyrosine kinases p60v-src and
`epidermal growth factor receptor [EGFR].’” Dec. 29 (quoting Ex. 1012,
`811) (emphasis added).
`
`7
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`Robinson determined that these compounds, administered alone, did not
`warrant further development is not dispositive in light of Akinaga’s
`teaching that a chemotherapeutic DNA damaging agent in combination with
`the tyrosine kinase inhibitor UCN-01 (as taught by Seynaeve) produces
`synergistic cytotoxic and antitumor effects.
`For the reasons set forth above, we did not overlook or misapprehend
`the evidence relating to Robinson.
`
`B.
`
`Akinaga 1991
`In our Decision, we were persuaded by Petitioner’s argument that one
`of ordinary skill in the art would have had a reason to combine Akinaga
`with Seynaeve, Tam, and Friedman “because they involve administration of
`the same tyrosine kinase inhibit (UCN-01) or its close structural analog
`[staurosporine], which has substantially similar effects on the cell cycle.”
`Dec. 37–38. In its Rehearing Request, Patent Owner argues that we
`misapprehended the evidence supporting Petitioner’s argument that “a
`person of ordinary skill would understand that a compound that inhibits v-
`src also would inhibit c-src” in light of Akinaga 1991.10 Reh’g Req. 7.
`According to Patent Owner, Akinaga 1991 demonstrated “significant
`differences in activity, selectivity, and potency” between “UCN-01 and
`staurosporine,” which is “compelling evidence that the mechanisms of
`action between UCN-01 and staurosporine are indeed different.” Id. at 8–9;
`see, e.g., Ex. 1035, Abstract (indicating that while staurosporine was 9 to 90
`times more potent at inhibiting growth of tumor lines in vitro, only UCN-01
`
`
`10 Shiro Akinaga et al., Antitumor Activity of UCN-01, a Selective Inhibitor
`of Protein Kinase C, in Murine and Human Tumor Models, 51 CANCER
`RES. 4888–92 (1991). Ex. 1035.
`
`8
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`showed antitumor effects in xenograft models). Patent Owner further
`argues that Akinaga 1991 ascribes these functional differences between the
`two molecules as the result of “a hydroxyl at the C-7 position of the
`indolocarbazole moiety of staurosporine.” Reh’g Req. 10.
`According to Patent Owner, Akinaga 1991 “shows that UCN-01 and
`staurosporine differ in a material way in mechanism of action and in
`structure, and thus people of ordinary skill in the art would not assume that
`UCN-01 and staurosporine have the same inhibitory behavior.” Id. at 2.
`Patent Owner, again, cites no expert testimony supporting its view of the
`understanding of one of ordinary skill in the art. In contrast, Dr. Eastman
`provided evidence that both molecules had similar effects on EGFR binding
`and were known to compete with ATP binding in the same way. Ex. 1002
`¶¶ 223–225. Because neither Dr. Eastman’s testimony, nor Petitioner’s
`arguments, demand that UCN-01 and staurosporine exhibit the same
`“activity, selectivity or potency,” as Patent Owner appears to suggest (see
`Reh’g Req. at 8–9), we credit Dr. Eastman’s testimony that: “As both
`staurosporine and UCN-01 were known to have this mechanism of action, a
`person of ordinary skill in the art would have logically predicted that UCN-
`01 would also inhibit EGF-stimulated tyrosine kinase activity.” Id. ¶ 224.
`
`Finally, Patent Owner asserts that Dr. Eastman’s reasons for
`combining the asserted references are “conclusory and refuted by record
`evidence,” because Akinaga 1993 and Tam showed that UCN-01 and
`staurosporine, respectively, showed different effects on cell cycle
`progression in different model systems. See Reh’g Req. 10–11.11 In
`
`
`11 Patent Owner also contends that at the Oral Hearing, we described
`Dr. Eastman’s reasons for combining the cited references as “pretty cryptic.”
`9
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`particular, Patent Owner notes that Akinaga showed that UCN-01,
`administered alone “arrested the cell cycle transiently at the G1 phase,”
`whereas Tam showed that staurosporine was able to override G2 arrest
`induced by DNA damage. See id. at 11. Patent Owner presents no
`persuasive evidence regarding how one of ordinary skill in the art would
`have viewed a comparison carried out under such diverse conditions. Nor
`does Patent Owner address Akinaga’s finding that in combination with a
`DNA damaging agent—conditions more akin to those of Tam—UCN-01
`resulted in a prolongation of the S (DNA synthesis) stage of the cell cycle.
`See Ex. 1004, 187 (“In contrast, the combination of both drugs caused a S
`phase prolongation of 48 h (Fig. 4D).”). Accordingly, based on the totality
`of the record, we accept Dr. Eastman’s testimony that one of ordinary skill
`in the art would have had reason to combine the cited references. See Dec.
`37.
`
`In view of the above, we did not overlook or misapprehend the
`evidence relating to Akinaga 1991.
`
`For the reasons given, it is
`
` ORDER
`
`ORDERED that Patent Owner’s Request for Rehearing is denied;
`
`FURTHER ORDERED that our Final Written Decision of September 11,
`2017, is republished solely to eliminate unintended font changes; Paper 43 is
`expunged.
`
`
`Reh’g Req 10. We disagree with Patent Owner’s interpretation as the
`transcript clearly shows that we were referring to Petitioner’s demonstrative
`slides 39 and 40. See Ex. 42, 38:10–16.
`10
`
`
`
`IPR2016-01034
`Patent 7,838,512 B1
`
`
`
`
`PETITIONER:
`WILMER CULTER PICKERING HALE and DORR LLP
`
`David L. Cavanaugh
`David.cavanaugh@wilmerhale.com
`
`Emily R. Whelan
`Emily.whelan@wilmerhale.com
`
`Heather M. Petruzzi
`Heather.petruzzi@wilmerhale.com
`
`MORRISON & FOERSTER LLP
`
`Matthew Kreeger
`mkreeger@mofo.com
`
`Matthew Chivvis
`mchivvis@mofo.com
`
`
`
`PATENT OWNER:
`
`Christopher Freking
`chris@ntknet.com
`
`
`11
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
