EUCLISES PHARMACEUTICALS, INC.

Patent Trials and Appeals Board

Mar 24, 2022

2021002861 (P.T.A.B. Mar. 24, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/401,777 01/09/2017 John J. TALLEY 16270-000034-US 3505 28997 7590 03/24/2022 Harness Dickey (St. Louis) 7700 Bonhomme, Suite 400 St. Louis, MO 63105 EXAMINER CRUZ, KATHRIEN ANN ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 03/24/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): bkamer@hdp.com stldocket@hdp.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JOHN J. TALLEY, BOBBY W. SANDAGE, and EDUARDO J. MARTINEZ Appeal 2021-002861 Application 15/401,777 Technology Center 1600 Before JEFFREY N. FREDMAN, JOHN E. SCHNEIDER, and RACHEL H. TOWNSEND, Administrative Patent Judges. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims directed to combinations of the chromene compound (S)-6-bromo-8-trideuteromethyl-2- (trifluoromethyl)- 2H-chromene-3-carboxylic acid and an inhibitor of PD-1, PD-L1 or CTLA-4 as obvious and for obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as Euclises Pharmaceuticals, Inc. (Appeal Br. 3.) Appeal 2021-002861 Application 15/401,777 2 STATEMENT OF THE CASE Appellant’s Specification notes that “COX-2 contributes to carcinogenesis by increasing production of prostaglandins, inhibiting apoptosis, promoting angiogenesis, and modulating inflammation and immune function.” (Spec. ¶ 4.) Appellant’s Specification also teaches that “[i]mmune checkpoint proteins are integral components of the immune system, which generally can act to stimulate or inhibit immune signals (e.g., the signal for T-cell activation).” (Id. ¶ 37.) And it further explains that “[m]any cancers express high levels of inhibitory immune checkpoint proteins to evade detection by T cells and other immune system components.” (Id. ¶ 38.) Appellant’s invention is directed to a composition that includes a particular COX-2 inhibitor combined with an inhibitor of a particular immune checkpoint protein. Claim 1 , reproduced below, is illustrative of the claimed subject matter: 1. A combination comprising: (S)-6-bromo-8-trideuteromethyl-2-(trifluoromethyl)-2H- chromene-3-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof and a second compound selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors , and CTLA-4 inhibitors. (Appeal Br. 16.) In response to a species election requirement, Appellant elected pembrolizumab, a monoclonal antibody that binds to PD-1, as the second Appeal 2021-002861 Application 15/401,777 3 compound. (See Non-Final Action 82.) Accordingly, as to the appealed obviousness rejection, we limit our analysis to the patentability of the elected species and the extent to which the rejected claims read on it. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI 1987). The prior art relied upon by the Examiner is: Name Reference Date McKearn et al. US 2002/0103141 A1 Aug. 1, 2002 Ayers et al. US 2016/0312297 A1 Oct. 27, 2016 Deepika Dhawan et al. Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells, 7(4) Mol. Cancer Ther., 897-904 2008 Yanmei Zhang et al. Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic Properties, 5 ACS Med. Chem. Lett. 1162-66 2014 2 The Examiner inadvertently states that this antibody binds to PD-L1. However, the Specification makes clear that this antibody binds to PD-1. (Spec. ¶ 59.) Appeal 2021-002861 Application 15/401,777 4 The following grounds of rejection by the Examiner are before us on review: Claims 1, 5, 7, 12, and 21 under 35 U.S.C. § 103 as unpatentable over Zhang, Dhawan, McKearn, and Ayers. Claims 1, 5, 7, 12, and 21 on the ground of non-statutory double patenting as being unpatentable over claims of U.S. Patent 9,371,305 and Ayers. DISCUSSION Obviousness (S)-6-bromo-8-trideuteromethyl-2- (trifluoromethyl)-2H-chromene-3- carboxylic acid, which formula is set forth below, is also known as A01. (Non-Final Action 8 (citing Spec. 12 (Table 1).) This compound is known to be a COX-2 inhibitor. (See Zhang Abstr.) The Examiner found that Zhang “teaches that COX-2 inhibitors have been used for treating various conditions including pain, inflammation, and certain types of cancer associated with inflammation mediated by COX-2.” (Non-Final Action 10 (citing Zhang 1162).) The Examiner explained that Zhang teaches creating deuterated benzopyran analogues for the purpose of finding COX-2 inhibitors with improved pharmacokinetic properties. (Id. at 9-10 (citing Zhang, Abstr.).) The Examiner further found that Zhang teaches A01, which it refers to as S-6h, is a potent COX-2 inhibitor. (Id. at 8, 11.) Appeal 2021-002861 Application 15/401,777 5 The Examiner found that Zhang tested the deuterated benzopyran analogue compounds in models of pain, inflammation and arthritis and determined that the compounds, including 6h, not only showed potency, but also “excellent selective COX-2 inhibition,” and “significantly improved PK profile.” (Id. at 11-12 (citing Zhang Tables 1 and 4, and Figure 2).) The Examiner further noted that Zhang teaches that the S-enantiomer of 6h, was 2-5 times more effective than the racemic mixture of the same compound. (Id. at 12 (citing Zhang 1165 and table 5).) The Examiner thus found that “Zhang clearly teaches the use of applicant’s elected compound A01, for use as a selective COX-2 inhibitor, as well as teaching the use of these compounds for treatment of cancers associated with inflammation mediated by COX-2.” (Id. at 13.) The Examiner relied on Dhawan for “show[ing] that bladder cancer was one of those cancers known to be mediated by COX-2, [and] in which COX-2 inhibitors had been used to treat.” (Id. at 9.) The Examiner stated that “Dhawan et al is generally drawn to the use of COX-2 inhibitors in treating bladder cancer” (id. at 13) and teaches that “COX-2 is overexpressed in ~75-85% of urinary bladder cancers” and “that the selective COX-2 inhibitor celecoxib has been shown to inhibit proliferation in HT1376 bladder cancer cell lines” (id. at 13-14 (citing Dhawan Abstr., 897). The Examiner noted that “Zhang compared their [deuterated benzopyran analogue] compounds to celecoxib and teaches that they were as potent, or more potent than celecoxib in the animal models a[t] inhibiting COX-2.” (Id. at 14.) The Examiner further noted that “McKearn is also drawn to the use of COX-2 inhibitors to treat bladder cancer and teaches the use of these in Appeal 2021-002861 Application 15/401,777 6 combination with other anti-cancer agents.” (Non-Final Action 9.) The Examiner recognized that McKearn is “generally drawn to treating various types of cancer with a combination of a COX-2 inhibitor and a DNA topoisomerase I inhibiting agent” but also “specifically teach[es] treating bladder cancer, with this combination.” (Id. at 14-15 (citing McKearn, Abstr., ¶¶ 697, 699).) The Examiner further found that McKearn teaches “a variety of different COX-2 inhibitors such as celecoxib, rofecoxib, and valdecoxib” as well as teaching “in one embodiment the selectivity ratio of COX-2 to COX-1 is at least 50 or at least 100.” (Id. at 15 (citing McKearn ¶¶ 97, 727).) The Examiner noted that “Zhang teaches a greater than 100x selectivity for COX2 and COX1 for the compound 6h” (Id. (citing Zhang Table 1).) The Examiner concluded from the foregoing teachings that the prior art teaches COX-2 inhibitors for treatment of bladder cancer “as well as teaching A01 (s-6h) as a preferred selective COX-2 inhibitor.” (Non-Final Action 19.) The Examiner relied on Ayers for its teaching of the anti-PD-1 antibody MK-3475, which is pembrolizumab, for use in treating cancers in which PD-L1 is expressed and “is correlated with poor prognosis and reduced survival,” such as bladder cancer. (Non-Final Action 93, Id. at 17- 18 (citing Ayers ¶¶ 3, 4, 18, 19, 192).) The Examiner noted that Ayers also teaches combination therapies with chemotherapeutic agents. (Id. at 18 3 The Examiner stated that MK-3475 is taught by Ayers to be a PD-L1 inhibitor. Ayers makes clear this antibody is a PD-1 antagonist, one that binds to PD-1 and inhibits the interaction of PD-L1 with PD-1. (Ayers ¶¶ 4, 17.) Appeal 2021-002861 Application 15/401,777 7 (citing Ayers ¶137).) The Examiner concluded from this that the prior art teaches “PD-L1 inhibitors for the treatment of bladder cancer, including teaching pembrolizumab (MK-3475) specifically as a preferred PD-L1 antagonist.” (Non-Final Action 19.) The Examiner determined that it would have been obvious to one having ordinary skill in the art to make a composition that combines both A01 and pembrolizumab for use as a combination therapy because both “are taught in the prior art to treat the same condition, and the combination requires nothing more than each compound having the effect already taught in the prior art as having,” i.e., compounds able to treat bladder cancer (Non- Final Action 22-23), which cancer is known both to overexpress COX-2 (id. at 20 (citing Dhawan and McKearn)), and PD-L1 (id.). We agree with the Examiner’s conclusion of obviousness. We note that the Examiner’s rejection starts with an examination of what is taught in Zhang. We, however, start with what is disclosed in Dhawan to address Appellant’s argument that “in the absence of any evidence that bladder cancer is amenable to treatment with a COX-2 inhibitor, there is no reason to select known COX-2 inhibitors based on their efficacy on COX-2 inhibition.” (Appeal Br. 6; Reply Br 2 (“Dhawan does not suggest that COX-2 inhibitors treat bladder cancer or have been shown to have anti- cancer activity against bladder cancer.”).) We disagree that there is an absence of evidence that bladder cancer is amenable to treatment with a COX-2 inhibitor. Moreover, we note that the Examiner’s exposition of the rejection as A in view of B, C, and D rather than the combination of teachings is of no significance. The question in this case is simply whether the claims define a Appeal 2021-002861 Application 15/401,777 8 patentable invention over the art cited by the Examiner. See In re Bush, 296 F.2d 491, 496 (CCPA 1961) (“[W]here a rejection is predicated on two references each containing pertinent disclosure which has been pointed out to the applicant, we deem it to be of no significance, but merely a matter of exposition, that the rejection is stated to be on A in view of B instead of on B in view of A, or to term one reference primary and the other secondary.”) Indeed, as in Bush we note that “[i]t would perhaps have saved much argument of the kind we have before us if the Patent Office had stayed with its rejection of the claims as unpatentable over A and B ‘considered together’ and had merely stated its reasons for such rejection without formal ali[gn]ment of the references.” Id. We provide below our reasons for disagreeing with Appellant that there is an absence of evidence that bladder cancer is amenable to treatment with a COX-2 inhibitor. Dhawan reports that COX-2 inhibitors have been shown to treat bladder cancer in a dog model that closely mimics human invasive bladder cancer. (Dhawan 897-898.) In particular, Dhawan reports: “[o]ur laboratory has observed antitumor activity of these drugs against experimentally induced bladder tumors in rodents and against naturally occurring invasive TCC in pet dogs, where the disease very closely mimics human invasive bladder cancer.” (Id. at 897-898.) Dhawan makes clear that “COX-2 is more than a bystander” in the process of carcinogenesis and cancer progression. (Dhawan 897.) Dhawan notes that COX-2 is overexpressed in various cancers and the antitumor effects of nonselective COX inhibitors and selective COX-2 inhibitors “in vivo have been reported.” (Dhawan 897.) Dhawan states that “complete and partial remission (overall remission rate 18%) and cancer stabilization (in Appeal 2021-002861 Application 15/401,777 9 55% of dogs) has occurred with COX inhibitor treatment.” (Id. at 898.) Dhawan’s teaching of antitumor effects in an animal model that closely mimics human invasive bladder cancer would have provided someone of ordinary skill in the art with a strong suggestion and reasonable expectation of success that human invasive bladder cancer can be treated with selective COX-2 inhibitors. For this reason, we do not agree with Appellant that “Dhawan does not disclose that bladder cancer can be treated with a COX-2 inhibitor” (Appeal Br. 6), or “[t]hat the Examiner offers no evidence demonstrating that bladder cancer can be treated with a COX-2 inhibitor in general” (Id.). Dhawan reports that the mechanism of action or pathways by which COX-2 inhibitors achieve antitumor effects is unclear. (Dhawan, Abstr., 898.) Dhawan explains that one of the major reasons this is unclear is because COX-2 inhibitors “do not have the same antitumor effects in standard in vitro assays as they have in vivo.” (Id. at 898.) Dhawan recognized that “[t]o optimally apply COX-2 inhibitors,” it was important to understand the mechanisms of the antitumor activity. (Id.) Dhawan explains that “standard in vitro assays do not seem useful for the study of inhibitory effects of COX-2 inhibitors, at clinically relevant drug concentrations” because “[t]o inhibit proliferation in standard in vitro assays, COX-2 inhibitors must be applied in very high concentrations; that is, concentrations far greater than those safely reached in serum in vivo.” (Id.) Because of this, the Dhawan authors undertook pilot studies to determine better in vitro assays for studying the antiproliferative activity of COX-2 inhibitors in vitro and with clinically relevant concentrations in various bladder cancer cell lines. In particular, Dhawan states “[p]ilot studies were initiated . . . to define Appeal 2021-002861 Application 15/401,777 10 appropriate conditions to study the antitumor effects of relevant concentrations of COX-2 inhibitors in vitro using bladder cancer cells” so as to be able to optimally apply COX-2 inhibitors to humans. (Dhawan 901; see also id. at 8984.) In carrying out these studies, the Dhawan authors noted “an important finding” of one of them: namely “that different bladder cancer cell lines responded differently to celecoxib” and thus “it is not possible to predict the antitumor effects of COX-2 inhibitors merely by the presence or absence of COX-2. This has been observed in studies of dogs with naturally occurring invasive TCC, in that the antitumor effects of COX inhibitors were not associated with the level of COX-2 expression in the cancer.” (Id. at 903 (emphasis added).) Nevertheless, Dhawan states (as recognized by Appellant (Reply Br. 2)) that from the studies carried out it was determined that “celecoxib inhibited the proliferation of human urinary bladder cancer cell lines by COX-2-dependent and COX-2-independent effects.” (Id. at 904.) Moreover, Dhawan reports from the result of all the studies performed That it seems the mechanism of action of celecoxib varies according to the capacity of the cell type being treated. Celecoxib effects depend not only on the conditions under which it is administered to the cells and to the cell type, but also on key players like COX-2, pRB, and pAKT. (Id. at 904.) These conclusions regarding celecoxib’s mechanism of action from in vitro cell line studies does not negate the fact that Dhawan clearly teaches the COX-2 inhibitors, and selective COX-2 inhibitors have resulted 4 Dhawan states: “several pilot experiments were done to assess the utility of different culture conditions in detecting COX-2 inhibitor antiproliferative activity in vitro. Then, studies were done to further define the effects of one such COX-2 inhibitor, celecoxib.” (Id. at 898.) Appeal 2021-002861 Application 15/401,777 11 in treatment of bladder cancer in an in vivo model. Nor has Appellant provided any Declaration evidence to the contrary. Given the foregoing, we do not agree with Appellant’s assertion that “there are fundamental uncertainties whether COX-2 inhibition would effectively treat bladder cancer at all given the variable results reported in Dhawan.” (Appeal Br. 7.) The “uncertainties” reported in Dhawan are not with respect to the fact that COX-2 inhibitors, including selective COX-2 inhibitors, have antitumor activity in urinary bladder cancer in vivo, and thus have in vivo treatment capability. Rather, the uncertainty is with respect to the mechanism of action by which COX-2 inhibitors provide anti-tumor benefits and finding an in vitro urinary bladder cell line in which to study the mechanisms of action contributing to the anti-tumor activity of selective COX-2 inhibitors known to be exhibited in vivo. And, the observations regarding the in vitro studies of Dhawan do not even establish that celecoxib does not result in anti-tumor effects in bladder cancer cell lines. Rather, they simply confirm what was believed to be the case from observations in studies of dogs having naturally occurring bladder cancer, that the anti- tumor activity would appear to involve a variety of mechanisms. (See Dhawan 903.) McKearn teaches, as the Examiner found, a combination of compounds to treat bladder cancer, where those compounds are a COX-2 selective inhibiting agent and a DNA topoisomerase I inhibiting agent. (McKearn ¶¶ 92, 693, 697-699.) McKearn notes that “the DNA topoisomerase I inhibiting agent and the cyclooxygenase-2 inhibiting agent together make a neoplasia disorder effective amount.” (Id. ¶ 92.) McKearn discloses that COX-2 selective inhibiting agents have inhibited tumor Appeal 2021-002861 Application 15/401,777 12 growth and metastasis in several in vitro and animal models and that “[t]he utility of COX-2 selective inhibiting agents as chemopreventive, antiangiogenic and chemotherapeutic agents is described in the literature.” (Id. ¶ 356.) And, McKearn discloses that COX-2 is overexpressed in bladder cancer lesions. (Id.) McKearn further discloses that therapeutic selective COX-2 inhibitors that are useful “have a selectivity ration of COX-2 inhibition relative to COX-1 inhibition of at least 50.” (Id. ¶ 97.) In light of the foregoing disclosures, we disagree with Appellant’s apparent suggestion that McKearn only teaches COX-2 inhibitors to be useful “‘for the prevention or treatment of DNA topoisomerase I inhibiting agent-related diarrhea.’” (Appeal Br. 7 (citing McKearn ¶ 93).) There is no dispute that Zhang describes A01, the claimed COX-2 inhibitor, or that Zhang demonstrates that A01 (a) has improved selectivity for COX-2 compared to celecoxib, (b) was potent in animal models of inflammation and arthritis, and (c) had a better PK profile then its non- deuterated counterpart and had the longest half-life of the deuterated benzopyran compounds studied. (See Zhang 1164-1165, and Tables 1, 4.) Zhang also states that there has been a “renewed interest in selective COX-2 inhibitors, particularly with coxibs5 that have a unique pharmacological profile, which could address unmet medical needs . . . includ[ing] treating pain and inflammation without further compromising renal function and in treating or preventing certain types of cancer associated with inflammation mediated by COX-2.” (Id. at 1162.) 5 Coxibs stands for COX-2 selective inhibitors. (Zhang 1162.) Appeal 2021-002861 Application 15/401,777 13 Although Zhang does not itself teach treating patients with urinary bladder cancer with A01, we conclude that the prior art cited by the Examiner, which we discussed above, would have provided one of ordinary skill in the art with a reason to select A01, a very selective COX-2 inhibitor, for use in a composition to administer as a treatment for urinary bladder cancer. Zhang provides data regarding the activity of A01 for COX-2 and its potency in inflammation and pain models, and suggests that such compositions could be useful in both treating pain and inflammation without further compromising renal function, as well as in cancer associated with inflammation mediated by COX-2. Dhawan teaches that selective COX-2 inhibitors have been shown to be efficacious in a model that very closely mimics human invasive bladder cancer. And McKearn teaches COX-2 is overexpressed in bladder cancer, as well as to use a selective COX-2 inhibitor with a selectivity of at least 50 to treat bladder cancer in conjunction with a DNA topoisomerase I inhibiting agent. Although McKearn may suggest an additional agent be combined with A01 in order to have a more effective composition for treating bladder cancer, we note that the claims on appeal do not preclude additional compositional elements. Moreover, the claims on appeal are directed to a composition, and do not require any particular efficacy in treating any cancer. Consequently, that McKearn may suggest a composition that is more efficacious than a COX-2 inhibitor alone in treating bladder cancer, does not teach away from a composition that does not include a DNA topoisomerase I inhibiting agent treatment. In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) (“A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.”); In Appeal 2021-002861 Application 15/401,777 14 re Mouttet, 686 F.3d 1322, 1334 (Fed. Cir. 2012) (“[J]ust because better alternatives exist in the prior art does not mean that an inferior combination is inapt for obviousness purposes.”). Appellant argues for the first time in the Reply Brief that the Examiner has failed to establish a motivation that one of ordinary skill in the art would have selected A01 for use in light of all the FDA-approved drugs and clinical trial drugs and pre-trial compounds that fall into the category of “COX-2 inhibitor” and that selectivity alone is insufficient given the structural differences between celecoxib and A01. (Reply Br. 2-3.) “[T]he reply brief [is not] an opportunity to make arguments that could have been made in the principal brief on appeal to rebut the Examiner’s rejections, but were not.” Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative). Appellant’s arguments advanced in such a manner in the Reply Brief have not afforded the Examiner an opportunity to respond to these new arguments. As stated in Ex parte Borden, consideration by the Board of new arguments presented for the first time in the Reply Brief that could have been presented earlier would “vitiate the force of the requirement in Board Rule 37(c)(1)(vii) that ‘[a]ny arguments or authorities not included in the brief . . . will be refused consideration by the Board, unless good cause is shown.”’ Id. Appellant has not demonstrated any specific Examiner findings presented for the first time in the Answer necessitating this specific new argument in rebuttal in the Reply Brief. Nor do we find any substantial differences in the Examiner’s initial findings and the Examiner’s findings stated in the Answer that would warrant the new arguments presented in the Reply Brief for the first time. (Compare Non-Final Action 8-25, with Ans. Appeal 2021-002861 Application 15/401,777 15 24-29.) We, therefore, base our decision only on those arguments timely raised in the opening Appeal Brief. Appellant does not dispute that Ayers teaches the use of pembrolizumab to treat bladder cancer or that it teaches combination therapies with chemotherapeutic agents. (See Appeal Br. 7-8) We agree with the Examiner that in light of the teachings described above, it would have been obvious to one having ordinary skill in the art to combine pembrolizumab with A01 together in a single composition with the reasonable expectation that it could be used to treat urinary bladder cancer. In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980). Asserted Unexpected Results Appellant urges that the Specification provides evidence of unexpected results. (Appeal Br. 8.) We only address those arguments relevant to the elected species A01, the claimed chromene compound which is a selective COX-2 inhibitor, and pembrolizumab, an anti-PD1 antibody which is a PD-1 inhibitor. Appellant urges that the “combination of Compound A01 with an anti-PD1 antibody (a PD-1 inhibitor) has a greater than additive effect in in vivo tumor models.” (Appeal Br. 8-10 (citing Fig. 2).) Figure 2 is reproduced below. Appeal 2021-002861 Application 15/401,777 16 Figure 2, above, shows the effect of Compound A01, an anti-PD1 antibody, or a combination thereof on tumor rejection in mice inoculated with colon carcinoma cells. Appellant explains that the administration of anti-PD-1 by itself to mice inoculated with CT26 colon carcinoma cells (solid smaller circles in Figure 2) did “not significantly improve tumor rejection,” nor did administration of A01 (denoted as ECP-1014) by itself at 1 mg/kg (gray triangle) or 10 mg/kg (gray inverted triangle). (Appeal Br. 8 (citing Fig. 2).) Appellant notes that administration of both A01 and anti-PD-1 “significantly improved the percentage of mice(> 75%) experiencing a tumor rejection (see dark gray triangles and dark gray inverted triangles).” (Id. at 9.) According to Appellant, “the anti-PD-L1 antibody utilized in the working examples are representative of all PD-1 and PD-L1 inhibitors. The improved efficacy of the combination of compound A01 with an anti-PD-L1 Appeal 2021-002861 Application 15/401,777 17 antibody shown in Example 4 can reasonably be extrapolated to all PD-1 inhibitors, all PD-L1 inhibitors, all CTLA-4 inhibitors, and combinations thereof.” (Id. at 12.) According to Appellant “[a]nti-PD-1 and anti-PD-L1 antibodies block the signaling through PD1 or PD-L1. This mechanism is consistent for all PD-1 and PD-L1 inhibitors-they block PD-1 or PD-L1 signaling, respectively.” (Id.) Appellant argues that “one of ordinary skill in the art would reasonably conclude that the effects seen in Figure 2 and in the specification as filed would extend to the entire scope of inhibitors recited in Claim 1.” (Id.) We provide the following observations regarding Appellant’s argument. First, we note that, in Example 2, the mice were not given a composition that included both A01 and the anti-PD1 antibody. The mice were administered compound A01 orally, whereas the anti-PD-1 antibody (identified as clone RMP1-14) was administered intraperitoneally. (Spec. ¶ 147.)6 Appellant’s claim is directed to a “combination comprising” both A01 and pembrolizumab, reasonably understood as requiring both compounds administered together. Thus, it is not clear that the Example 2 data provides information relevant to the “claimed invention.” In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“One way for a patent applicant to rebut a prima facie case of obviousness is to make a showing of ‘unexpected results,’ i.e., to show that the claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected.”). 6 This was also the manner in which Example 4 was carried out with A01 and an anti-PD-L1 antibody, identified as clone 10F9G. (Spec. ¶ 154) Appeal 2021-002861 Application 15/401,777 18 Second, according to Appellant’s argument, the results of Example 4 can be extrapolated to all PD-1 inhibitors, all PD-L1 inhibitors, and all CTLA-4 inhibitors claimed. However, Appellant’s own Specification does not support such a conclusion. The results reported for Example 2 (PD-1 inhibitor) and 4 (PD-L1 inhibitor) are not the same. Regarding Example 4, it is stated that the anti-PD-L1 antibody administered alone and compound A01 administered alone slowed tumor growth. (Spec. ¶ 155.) Regarding Example 2, however, it is stated that “monotherapy (celecoxib, compound A01, or anti-PD1 antibody alone) did not prevent tumor growth (Figure 2).” (Id. ¶ 148.)7 An additional difference exists if one considers Appellant’s argument regarding Example 2, that “the combination of Compound A01 with an anti- PD1 antibody (a PD-1 inhibitor) has a greater than additive effect in [the] in vivo tumor model.” (Appeal Br. 8-9 (emphasis added).) Appellant notes that administration of the combination of A01 (at both doses) with anti-PD-1 “significantly improved the percentage of mice(> 75%) experiencing a tumor rejection (see dark gray triangles and dark gray inverted triangles).” (Appeal Br. 9.) In contrast, regarding Example 4, Appellant states simply that “Table 11 shows that the administration of a combination of Compound 7 We cannot compare the data itself from Example 2 and Example 4. That is because the data results reported in Example 4 are size of tumor after 16 days (Spec. ¶ 156 (Table 11 (tumor growth being reported in mm3)). For Example 2, however, it appears that the data reported from whatever measurements were taken over 50 days is the number of mice rejecting tumor. (Spec. ¶ 148 (identifying that mice “completely rejected the tumor” with combination therapy but monotherapy “did not prevent tumor growth” in the treated mice; see also id. at Fig. 2 (y-axis is “Percentage of tumour rejection”).) Appeal 2021-002861 Application 15/401,777 19 A01 with an anti-PD-Ll antibody reduced the tumor volume relative to the tumor volumes from mice receiving Compound A01 or the anti-PD-LI antibody alone.” (Id. at 10.) There is no statement that the reduction is greater than additive, as Appellant asserts in the brief was achieved with the anti-PD1 antibody, pembrolizumab, in combination with A01. Thus, even Appellant’s statements in the brief regarding the specific examples in the Specification do not support its argument that the results of Example 4 can be extrapolated to all PD-1 inhibitors, all PD-L1 inhibitors, [and] all CTLA- 4 inhibitors,” as claimed (Appeal Br. 12).8 8 Regarding Example 4, it is not even clear that Appellant’s Specification demonstrates that an anti-PD-L1 inhibitor in combination with A01 provides effects that are better than with monotherapy. Indeed, the Specification does not state as much. All that is stated is that “[t]reatment with Compound A01 slowed or anti-mPD-L1 slowed tumor growth compared to vehicle and isotype controls.” (Spec. ¶ 155.) We reproduce Table 11 from Appellant’s Specification below and note that “(all doses are 10 mg/kg except where indicated)” (id.) We note that tumor growth at Day 16 for control antibody was 1297 mm3 and for vehicle was 2001 mm3. For combination therapy of 10 mg/kg A01 and anti-PD-L1 tumor growth at Day 16 was 896 mm3. For Appeal 2021-002861 Application 15/401,777 20 In light of the foregoing, which contradicts Appellant’s position “that the results for the anti-PD-LI antibody utilized in the working examples are representative of all PD-1 and PD-LI inhibitors” (Appeal Br. 12), we cannot conclude that Appellant’s data obtained using pembrolizumab and A01 is even representative of all PD-1 inhibitors. Finally we note that Example 2 itself does not report that the results of combination therapy are greater than additive. Indeed, as we noted in footnote 7, Figure 2 appears to report only the percentage of mice treated that rejected the tumor not the percentage in terms of size of tumor reduction that was achieved by the different therapies. It is not clear that one of ordinary skill in the art would reasonably conclude from the reported data depicted in Figure 2 from Example 2 that one therapy was greater than additive compared to any other therapy. And, Appellant does not provide declaration evidence in support of its conclusion, only attorney argument monotherapy with 10 mg/kg, A01 tumor growth at Day 16 was measured at 759 mm3 (which is smaller than was measured for combination therapy) and for anti-PD-L1 antibody at 10 mg/kg, tumor growth at Day 16 was measured at 849 mm3 (which, again, is smaller than for combination therapy). Thus, the data at Day 16 demonstrates that the combination therapy with 10 mg each of A01 and anti-PD-L1 antibody does not reduce tumor growth to the same extent as monotherapy. Moreover, for combination therapy of 1 mg/kg A01 and 10 mg/kg anti-PD-L1, at Day 16, tumor growth was measured at 797 mm3, which is somewhat smaller than with 10 mg/kg anti-PD-L1 monotherapy, but is somewhat larger than with 10mg/kg A01 monotherapy. There is no data for 1 mg/kg A01 monotherapy. But the data does not seem to show even additive results at Day 16, just that the combination therapy might be somewhat better than anti-PD-L1 monotherapy. We are not apprised of whether the difference is statistically meaningful. Appeal 2021-002861 Application 15/401,777 21 (Appeal Br. 9). “Attorney’s argument in a brief cannot take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). Thus, for the foregoing reasons, we do not find that Appellant’s Specification demonstrates unexpected results with respect to the claimed invention that we are reviewing on appeal, i.e., a combination of pembrolizumab with the chromene (S)-6-bromo-8-trideuteromethyl-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid. In light of the above, we affirm the Examiner’s rejection of claim 1, limited to the elected species pembrolizumab as the second compound, under 35 U.S.C. § 103 as unpatentable over Zhang, Dhawan, McKearn, and Ayers. Claims 5, 7, 12, and 21 have not been argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). Non-statutory Double Patenting The Examiner found that the ’305 patent claim 15 recites the chromene compound set forth in claim 1 on appeal. (Non-Final Action 26.) The Examiner notes that the claims of the ’305 patent “do not require the pembrolizumab” but that “they do not exclude pembrolizumab.” (Id.) The Examiner finds that “[t]he ’305patent teaches using [the chromene] compositions as COX-2 inhibitors and teaches the use of these for treating various cancers including bladder cancer (see column 6, lines ~15-35).” (Id. at 27.) In addition, the Examiner finds that Ayers teaches using MK-3475 to treat bladder cancer. (Id.) The Examiner determines that it would be obvious to combine the compounds of the ’305 patent which are taught to be used for treating cancer with other known compositions for treating bladder cancer. Appeal 2021-002861 Application 15/401,777 22 (Id.) The Examiner concludes therefore, that “the claimed invention is not distinct from the invention disclosed in 9,371,305 and that patent would render the claimed compositions obvious.” (Id.) We agree with Appellant that the Examiner’s rejection improperly relies on the Specification of the ’305 patent to justify the conclusion of patentable indistinctness between the claims of the ’305 patent and those on appeal here. “As a general rule, obviousness-type double patenting determinations turn on a comparison between a patentee’s earlier and later claims, with the earlier patent’s written description considered only to the extent necessary to construe its claims.” Eli Lilly & Co. v. Teva Parenteral Meds., 689 F.3d 1368, 1379 (Fed. Cir. 2012). The disclosure of the earlier patent is not generally considered “because the non-claim portion of the earlier patent ordinarily does not qualify as prior art against the patentee and because obviousness-type double patenting is concerned with the improper extension of exclusive rights - rights conferred and defined by the claims.” Id. We note that there is “a limited exception to this customary framework.” Id. That exception is in “the situation in which an earlier patent claims a compound, disclosing the utility of that compound in the specification, and a later patent claims a method of using that compound for a particular use described in the specification of the earlier patent” and the “‘use’ [being claimed in the later patent] constituted a, or the, disclosed use for the previously claimed substance.” Id. The Examiner does not turn to the Specification of the ’305 patent for construing any claim terms, and this case does not present the limited exception for consulting the Specification. Without turning to the Appeal 2021-002861 Application 15/401,777 23 Specification of the ’305 patent, the Examiner’s stated rejection does not provide sufficient evidence to substantiate a reason to combine MK-3475 taught in Ayers with the chromene compound set forth in claim 15 of the ’305 patent. Consequently, we do not affirm the Examiner’s rejection of claims 1, 5, 7, 12, and 21 on the ground of non-statutory double patenting as being unpatentable over claims of U.S. Patent 9,371,305 and Ayers. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 5, 7, 12, 21 103 Zhang, Dhawan, McKearn, Ayers 1, 5, 7, 12, 21 1, 5, 7, 12, 21 Non-statutory Double Patenting: US 9,371,305, Ayers 1, 5, 7, 12, 21 Overall Outcome 1, 5, 7, 12, 21 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED