DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the first action on the merits.
Election/Restrictions
Applicant’s election of Group (I) in the reply filed on March 15, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Group (I), drawn to compositions comprising an inhibitor of the P2X4 receptor or an inhibitor of the P2X4 receptor signaling pathway in combination with a cell death inducing chemotherapeutic drug and/or cell death inducing therapy, embraced by claims 1-3 and 16 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant further elected the following species: NC-2600 as a specific
inhibitor of the P2X4 receptor, and 5-fluorouracil (5-FU) as a cell death inducing chemotherapeutic drug and/or cell death inducing therapy. The Examiner has determined claims 1-3 read on the elected species.
Claims 1-3 and 8-18 are pending and claims 1-3 are under consideration. Claim 16 is withdrawn based on the species election and claims 8-15, 17 and 18 are withdrawn based on the restriction requirement.
Claim Rejections - 35 USC § 112
The rejections of claims 2 and 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the term “Carbamazepine der” and the phrase, “modified versions of these inhibitors” are withdrawn based on the amendments.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-3 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over He et al. (Cells, 2020, 9(11), 2511, cited on IDS) in view of Marketscreener (2016, <Nippon Chemiphar : Neuropathic Pain Drug P2X4 Receptor Antagonist NC-2600 Moves into Phase 1 Clinical Trial (pdf, 127KB) | MarketScreener> downloaded on March 30, 2026) and Longley et al. (Nat Rev Cancer 3, 330–338 (2003).
The present application claims a composition comprising an inhibitor of the P2X4 receptor or an inhibitor of the P2X4 receptor signaling pathway in combination with a cell death inducing chemotherapeutic drug and/or cell death inducing therapy, wherein the inhibitor of the P2X4 receptor is NC-2600 and the cell death inducing chemotherapeutic drug is 5-fluorouracil (5-FU).
He et al. teach “Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target,” see title of the reference.
Marketscreener identifies NC-2600 as a P2X4 inhibitor, see title, “Nippon Chemiphar : Neuropathic Pain Drug P2X4 Receptor Antagonist NC-2600 Moves into Phase 1 Clinical Trial.
He et al. nor Marketscreener teach a combination of NC-2600 and 5-FU.
However, Longley teaches 5-FU is a well-known anti-tumor agent and is used in combination therapies, see page 330, left-hand column, second paragraph, among other citations in the reference.
It has been held that combinations of two or more compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960).
Therefore, it would have been obvious at the time of filing to combine these anti-cancer agents with the expectation that such a combination would be effective in treating cancer. Thus, combining them flows logically from both having been individually taught in prior art.
Thus, said claims are obvious.
The rejection may be overcome by submitting unexpected results commensurate in scope with the claimed subject matter.
Applicant traverses by stating, “None of the cited references teach or suggest the specific combination of a P2X4 inhibitor with a cell death-inducing chemotherapeutic drug and/or cell death inducing therapy for preventing and/or treating a solid tumor or metastases as recited in the claims.”
This is not persuasive. These are properties of the compounds. MPEP 2112 states, “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Applicant further states, “The mere fact that 5-FU is a known anti-cancer agent does not provide a reason for one skilled in the art to specifically select 5-FU to combine with NC-2600 or other P2X4 inhibitors. One skilled in the art would know that there exist at least hundreds of known FDA-approved anti-cancer agents and even thousands more in early-stage research, clinical trials, or as experimental compounds. The He et al., Marketscreener and Longley et al. references do not provide any teaching or suggestion that would have led one skilled in the art to specifically select 5-FU and combine it with NC-2600 or other P2X4 inhibitors.”
This is also not persuasive. As noted in the rejection, combining compounds that are known in the art to treat the same disease, disorder or condition, is obvious. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07.
Applicant further states, “Unlike in BTG International Ltd. v. Amneal Pharmaceuticals LLC, 923 F.3d 1063, 1073-76 (Fed. Cir. 2019), where the Federal Circuit affirmed obviousness only because the prior art specifically taught combining abiraterone acetate with prednisone, explaining both the therapeutic rationale and the expected benefits of the particular combination, the He et al., Marketscreener and Longley et al. references contain no teachings that provide a reason for the particular combination, as recited in the Applicants' claims. The obviousness of a pharmaceutical combination depends on evidence providing a specific reason to combine the particular therapeutic agents, not merely the fact that each drug was independently known to treat cancer. BTG International Ltd. v. Amneal Pharmaceuticals LLC, 923 F.3d 1063, 1073-76 (Fed. Cir. 2019).”
This is also not persuasive. The PTAB and district court relied on prior art showing that abiraterone had an anticancer effect, and that prednisone, while primarily a corticosteroid, could have its own anti-cancer effect or be used palliatively to reduce side effects in prostate cancer treatment. The court emphasized that the prior art provided a reasonable expectation that prednisone could be used as a therapeutic agent in prostate cancer. This meant that combining abiraterone with prednisone was not a surprising or inventive step, it was a logical extension of known uses. Because both components were already known in the art, the Federal Circuit concluded the combination was obvious. The combination was predictable and would have been within the skill of the person having ordinary skill in the art.
Applicant further states, “In the absence of such teaching or suggestion, there is no reason for one skilled in the art to specifically select the Longley et al. reference and combine it with the He et al. and Marketscreener references. Any conclusion that the claimed combination would have been obvious is, therefore, based on hindsight rather than evidence of a motivation to combine.
The obviousness inquiry must guard against slipping into the use of hindsight and resist the temptation to read into the prior art the teachings of the invention at issue. Abbott Labs. v. Sandoz Inc., 544 F.3d 1341, 1347 (Fed. Cir 2008).”
This is also not persuasive. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant further states, “The specification teaches, in the paragraph bridging pages 9 and 10, that
The present invention is based on the surprising finding that tumor cells -
when killed during chemo- and/or toxin therapy - release messenger compounds, in particular ATP, into the tumor environment that improve survival of the neighboring tumour cells based on the functions of mTOR and P2x4. Therefore, the preventive and/or therapeutic treatment in context of the invention is based on a combinatorial approach of inhibiting the ATP-dependent P2X4 receptor- and/or P2X4 receptor signaling pathway-mediated tumor escape mechanism(s) together with the toxicity of the amount of a cell death inducing chemotherapeutic drug and/or a cell death inducing therapy. This combination (optionally with other agents as disclosed herein), as exemplified by the preferred combination of 5-FU and 5-BDBD, effectively blocks this escape-mechanism, and with it a further growth of the tumor and/or the formation of metastases or a relapse.
The specification defines the panel of combination drugs, on page 11, 2nd paragraph, to be
"suitable cell death inducing chemotherapeutic drug and/or a cell death inducing therapy can be used in the context of the present invention, as long as it can be combined (either provided together with, jointly, or separately as long as functioning together in the subject) with the above inhibitor of the P2X4 receptor inhibitor of the components of the P2X4 receptor signaling pathway."
The specification also teaches, on page 21, last paragraph, that:
The inventors' experiments revealed how an increased ATP release from
dying tumor cells (because of cell death inducing chemotherapeutic drugs and/or a cell death inducing therapy) activates mTOR survival signals in adjacent tumor cells in a P2X4 receptor dependent manner. This activation is essential for counteracting an increase of pro-apoptotic ROS signals in the tumor in order to help remaining tumor cells to escape cell death and to maintain tumor integrity (Fig. 4k). These findings open up a new strategy for an effective treatment and/or prevention of solid tumors, and metastases.”
This is also not persuasive. Again, if the combination of the elected compounds is administered, these properties would still be obtained. MPEP 2112 states, “"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
The fact that Applicant may have found a new mode of action to treat a tumor or metastases does not change the combination is obvious.
Applicant further states, “Evidence that the claimed invention is unexpectedly superior in one of a spectrum of common properties over the prior art can be enough to establish non-obviousness. See In re Rouffet, 149 F.3d 1350, 1355 (Fed. Cir. 1988); In re Sebek, 465 F.2d 904, 907 (C.C.P.A. 1972), In re Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987).
The specification further shows, in Fig 3k, that the combination results in a considerable improvement of the activity of 5-FU. In addition, the specification shows in two examples (5-BDBD and doxycycline-inducible shRNA, even in vivo) that the addition of a drug to the specific P2X4 inhibitors significantly improves the effect thereof.”
This is also not persuasive. Indeed, Figure 3k, see below, provides an unexpected result when 5-FU is combined with 5-BDBD.
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However, the claims are not commensurate in scope with the data provided in Figure 3k. The assay was completed at a particular concentration of both components and with AOM/DSS and APTAK tumor organoids, specific for colorectal and KRAS mutated cancers.
MPEP 716.02(D) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
Thus, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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