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 .
DETAILED ACTION
Applicant’s election of Group 1, claims 1-11 and 20 in the reply filed on December 9, 2025 is acknowledged.
Applicant’s election of species: 1) head and neck squamous cell carcinoma (HNSCC) as the specific cancer; 2) anti-PD-1 antibody as the specific agent blocking signaling through PD-1; 3) PTC596 as the specific BMI-1 inhibitor, in the reply filed on December 9, 2025 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)). Thus, the requirement is made FINAL.
Claims 12-19, 21-28, 30-34, and 41-44 were previously canceled.
Claims 1-11, 20, 29, 35-40 and 45 are pending.
Claims 7, 8, 29, 35-40 and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1-6, 9-11 and 20 are pending and under consideration.
Priority
It is acknowledged that this application is a National Phase Application of PCT/US2021/035735 filed June 3, 2021, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 63/034,818 filed June 4, 2020. The priority date has established as June 4, 2020.
Information Disclosure Statement
The Information Disclosure Statement filed on 02/13/2023 has been considered and entered by examiner.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color, for example in the Specification of 11/30/2022: [0015] Figures 2A-2N; [0016] FIGS. 3A-3L; [0017] FIGS. 4A-4K; [0018] FIGS. 5A-5J; [0019] FIGS. 6A-6L; [0020] FIGS. 7A-7Q; [0021] FIGS. 8A-8B; [0023] FIGS. 10A-10G; [0024] FIGS. 11A-11F; [0027] FIGS. 14A-14I; [0028] FIGS.15A-15I; [0030] FIGS. 17A-17B; [0031] FIGS. 18A-18B. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites: “wherein said anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, and atezolizumab”. However, avelumab, durvalumab, and atezolizumab are antibodies that bind to PD-L1 (a ligand of PD-1). Thus, the scope of “anti-PD-1 antibody” is unclear. One of ordinary skill in the art would not consider an anti-PD-L1 antibody as an anti-PD-1 antibody.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 9-11 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to a method of treating cancer in a patient in need thereof, comprising the steps of i) administering to said patient an agent that blocks signaling through programmed cell death protein 1 (PD-1); and ii) administering to said patient an agent that reduces expression or function of B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1). Given Broadest Reasonable Interpretation (BRI), the claim encompass: 1) a broad genus of agents blocking signaling through PD-1 which may have different structures (e.g., a protein, nucleic acid, or a small molecule) and may target to different genes in the PD-1/PD-L1 signaling pathway; and 2) a broad genus of agent reducing expression or function of BMI-1 which may have different structure (e.g. small molecule, peptide, antibody, oligonucleotide, genome editing system) and target different genes in BMI-1 pathway. In addition, based on paragraphs [0052] and [0053] of the instant publication US 2023/0233566 A1, the claim encompass agents which are currently unknown (“will be developed in the future”).
The instant specification provided limited evidence of the effect of a few combinations comprising an agent blocks signaling through PD-1 and an agent reducing expression or function of BMI-1 for treating BMI-1 positive cancers (e.g. HNSCC):
Example 1 shows an anti-PD-1 antibody (BioXcell, Cat #BP0089) in combination with PTC209 eliminates CSCs and inhibits HNSCC progression ([0095] of the instant publication US 2023/0233566 A1).
Example 1 shows BMI-1 knock out by siRNA + anti-PD1 induced apoptosis of HNSCC, exhibited inhibitory effects on lymph node metastasis, and induced CD8+ T cell infiltration in HNSCC ([0097] of the instant publication US 2023/0233566 A1).
Example 1 shows an anti-PD-1 antibody (BioXcell, Cat #BP0089) in combination with PTC209 prevent relapses of HNSCC ([0103]).
Thus, the specification teaches two combinations (PTC209 + anti-PD-1 antibody; BMI-1 siRNA + anti-PD-1 antibody) to BMI-1 positive cancer: e.g. HNSCC. Thus, the specification lacks written description support for the broadly claimed methods which encompass very broad genus of combinations.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of afunctional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Regarding “an agent that blocks signaling through programmed cell death protein 1 (PD-1)”, as set forth above, the claims encompass a broad genus of agents which may be any types of molecule, e.g. a protein, nucleic acid or a small molecule. These compounds could have different structures (antibody, peptide, small molecule, RNA, DNA, etc.), different physical/chemical properties, and function through different mechanisms. Paragraphs [0051] of the instant publication US2023/00233566 A1 only teach a number of antibodies to PD1 or PD-L1. However, these antibodies to PD1/PD-L1 axis do not teach the structure of other types of agents encompassed by the claims (such as small molecule antagonists, or antibodies yet to be discovered). These known antibodies to PD1/PD-L1 do not teach the structure (such as CDRs) of novel antibodies to PD-1/PD-L1. In addition, antibody antagonists to PD1/PD-L1 axis and other types of antagonists have different therapeutic properties, such as specificity, pharmacodynamics. Thus, one of ordinary skill in the art would not be able to readily visualize or recognize other types of inhibitors to PD1/PD-L1 signaling (other than known anti-PD1 and anti-PD-L1 antibodies such as the antibodies of instant claim 6 and the one used in Example 1) in combination with an inhibitor BMI-1 would lead to the same outcome as showed in the Examples of the instant specification.
Regarding “an agent that reduces expression or function of BMI-1”, paragraphs [0059] of the instant publication describes siNRAs specific for BMI-1. In addition, paragraphs [0053-0058] describe several small molecule can reduce expression or function BMI-1, including PTC209, PTC596, PRT4165, PTC-209 HBr, and PTC-028; paragraphs [0059] describes siNRAs specific for BMI-1. However, the instant specification has not provided a sufficient description about the correlation between the recited functions (such as reducing function of BMI-1, reducing BMI-1 positive cancer stem cells) and the structure of inhibitors. Therefore, the agents (e.g. small molecule BMI-1 inhibitors) described in the specification do not teach the structure of new agents (e.g. other small molecule BMI-1 inhibitors) that reduces expression or function of BMI-1. Paragraph [0053] states: “the agent that reduces expression or function of BMI-1 is a BMI-1 inhibitors. The present disclosure encompasses BMI inhibitors that are currently in use, in development, or those that will be developed in the future”. As set forth above, because based on the specification and prior art, one of ordinary skill in the art would not be able to readily recognize/visualize a novel BMI-1 inhibitor. Thus, the specification fails to convey with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant has the possession of the broadly claimed BMI-1 inhibitors.
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of§ 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004). Meeting the written description threshold requires showing that the applicant was in "possession" of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning - i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims. Given the claimed broadly class of antibody binding domains, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish "a reasonable structure-function correlation" either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutsch/and GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the "limitations above" and then identifying those that satisfy claim limitations, but mere "wish or plan" for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibody binding domains to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017).
Claims 2-6, 9-11 and 20 also encompass 1) a broad genus of agents blocking signaling through PD-1; and/or 2) a broad genus of agent reducing expression or function of BMI-1. Thus, these claims also lack written description support.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, and 10 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Shemi (Shemi et al., US 2020/0115712 A1, Publication Date: 04/16/2020).
Shemi teaches that agents blocking PD-1/PD-L1 checkpoints have demonstrated a significant clinical response in some solid tumors. However, many patients do not respond to such therapies. The reasons for resistance are associated with the limited infiltration of cytotoxic T-cells. There is an urgent need to accelerate infiltration of T cells including CD8+ and CD4+ and of NK and NKT cells into tumor cores ([0004]).
Shemi teaches a method for treating a solid cancer comprising administering a polymeric drug delivery device (DDD) comprising a chemotherapeutic agent and an immunotherapy composition (claim 10, [0079-0085]), wherein the chemotherapeutic agent is a nucleic acid, peptide, small molecule, or antibody (claim 12), such as RNAi agent (claim 13).
Shemi teaches that the RNAi agent can be a BMI1 siRNA (Fig. 1D). BMI1 siRNA would read on an agent that reduces expression or function of BMI1.
Shemi teaches that BMI-1 siRNA induces increased tumor necrosis (Fig. 1D and [0155]).
Shemi teaches sequences of BMI1 siRNAs ([0022] and [0023]).
Shemi teaches the immunotherapy composition is at least one of a PD-1 inhibitor (claim 17), such as nivolumab, pembrolizumab (claim 18). Thus, Shemi teaches a method of treating cancer comprising administering a BMI-1 inhibitor (BMI-1 siRNA) and an anti-PD-1 antibody.
Regarding claim 2, Shemi teaches examples of solid tumor, including pancreatic cancer, breast cancer, small cell lung cancer, prostate cancer ([0046]).
Regarding claim 3, Shemi teaches inhibiting metastasis of a tumor in a subject ([0063]). In addition, “reduces metastasis of said cancer in said patient” recited is merely intended result of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, the result of claim 3 are given no weight. A “reduces metastasis of said cancer in said patient” is inherited with the method taught by Shemi.
Regarding claim 4, “wherein said method reduces the number of BMI-1+ cancer stem cells” recited is merely intended result of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, the result of claim 4 are given no weight. A “reduces the number of BMI-1+ cancer stem cells” is inherited with the method taught by Shemi.
Regarding claims 5 and 6, Shemi teaches the immunotherapy composition is at least one of a PD-1 inhibitor (claim 17), such as nivolumab, pembrolizumab (claim 18).
Regarding claim 10, Shemi teaches that DDD is administered prior to or concurrently with the administration of the cancer immunotherapeutic agent ([0057]). In addition, those are only three possible options for administering agent of (i) and agent of (ii) in combination.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 9-11 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al., Cancer Cell Int., (2017) 17: 107, Publication Date: 11/21/2017) in view of Lin (Lin et al., Frontiers in Oncology, Volume 8, Article 532, Publication Date: 11/21/2018).
Wang teaches that aberrant over-expression of BMI1 has been found in various cancers, including lung, liver, breast and head neck cancers (page 2, col. 1, para. 2).
Wang teaches that BMI1 plays critical and indispensable roles in governing self-renewal capacity malignant cancer stem cells (CSC) which has been increasingly recognized to largely responsible for cancer initiation, therapeutic resistance, disease relapse and metastatic dissemination (page 2, col. 1, para. 2).
Wang teaches genetic silencing and pharmacological inhibition of BIM1 induced apoptosis and senescence, enhanced chemosensitivity, and diminished invasive and metastatic potentials, thus ultimately compromised cancer progression (page 2, col. 1, para. 2).
Wang teaches that BMI1 is overexpressed in a subset of HNSCC samples (the bridging paragraph of cols. 1-2 on page 4, and Fig. 1).
Wang teaches that PTC-209 reduces BMI1 expression in HNSCC cell lines (Figs. 2a and 2b, and the bridging paragraph of pages 4-5).
Wang teaches that PTC-209 inhibited cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis in HNSCC cells (Figs 3a-3e).
Wang teaches that the number of tumorsphere formed in vitro was significantly decreased upon PTC-209 addition. Noticeably, secondary tumorsphere formation was also remarkably impaired in PTC-209 treated cells, thus suggesting the self-renewal properties were compromised in HNSCC cells treated with PTC-209 (Fig. 5a and 5b; and the bridging paragraph of cols. 1-2 on page 8).
Wang teaches that PTC-209 treatment also resulted in remarkable down-regulation of several cancer stem cell (CSC) markers and modulators such as CD44, CD133, Sox2, Nanog (Fig. 5e, and the bridging paragraph of cols. 1-2 on page 8).
Wang teaches that PTC-209 administration significantly retarded and impaired HNSCC tumor (the elected species) growth in HNSCC xenograft model. Moreover, putative HNSCC CSCs marker CD44 revealed that the number of CD44-positive cells was much less in PTC-209 treated samples in relative to controls (Figs. 6a-6d, and § Pharmacological inhibition of Bmi1 by PTC-209 impaired HNSCC overgrowth in vivo).
Taken together, Wang teaches pharmacological targeting of BMI1 (e.g. administering PTC-209) resulted in impaired cell proliferation, migration and invasion, increase cellular apoptosis and reduced CSC subpopulation in HNSCC (also see, page 11, col. 1, para. 2). However, Wang does not teach in combination with an agent that blocks signaling through PD-1.
Lin teaches that HNSCC exhibits an enriched tumor immune landscape, and when HNSCC showed a clinical progression, the immune response elicited by the strong immunogenicity of HNSCC is usually suppressed. Immunosuppressive cells such as bone marrow-derived suppressor cells (MDSCs), M2-type tumor associated macrophages (TAMs), and regulatory T cells (Tregs) can build an immunosuppressive state in HNSCC microenvironment (TME). The blockade of PD-1/PD-L1 could reduce the population and activities of MDSCs and Tregs, and restore the cytotoxicity of T cells and NK cells, ultimately relieving the tumor immune escape and inhibiting tumor growth. (page 2, col. 1, para. 2).
Lin teaches that FDA has approved the PD-1 targeted monoclonal antibody: pembrolizumab and nivolumab for the treatment of R/M HNSCC. The new edition of the National Comprehensive Cancer Network incorporated these two drugs for the treatment of HNSCC. Compared with traditional therapies, the emerging PD-1 blockade immunotherapy exhibited an encouraging therapeutic efficacy for patients with advanced HNSCC (page 2, col. 1, para. 2).
Lin teaches that PD-1/PD-L1 blockade has shown a desired and long-lasting therapeutic effect in the treatment of HNSCC, but only a small number of patients with HNSCC can benefit from PD-1/PD-L1 monotherapy (Abstract).
Lin teaches that combining the anti-PD-1 treatment with other treatment options for HNSCC has become a commonly used strategy and may lead to synergistic effects (Abstract, and Fig. 1).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to modify the method of treating HSNCC with a BMI inhibitor (PTC-209) taught by Wang by using PTC-209 in combination with an anti-PD-1 antibody such as pembrolizumab or nivolumab, because Lin teaches pembrolizumab or nivolumab are approved for treating HNSCC by FDA, HNSCC TME shows an immunosuppressive state; combination therapy is well-known and widely-applied strategy in cancer treatment. One of ordinary skill in the art would have a reasonable expectation of the combination would have increased therapeutic activity because the treatment combines two different mode-of-actions against HNSCC. The motivation would have been to develop a new and more powerful treatment for HSNCC.
Regarding claim 3, Wang teaches that expression of overexpression of BMI1 facilitated metastatic spreading (page 2, col. 1, para. 2). One of ordinary skill in the art would have expected that the combination taught by Wang and Lin (PTC-209 + pembrolizumab or nivolumab) would be able to reduce metastatic spreading of the cancer in the patient.
Regarding claim 4, Wang teaches that PTC-209 administration significantly retarded and impaired HNSCC tumor (the elected species) growth in HNSCC xenograft model. Moreover, putative HNSCC CSCs marker CD44 revealed that the number of CD44-positive cells (CSC cells) was much less in PTC-209 treated samples in relative to controls (Figs. 6a-6d, and § Pharmacological inhibition of Bmi1 by PTC-209 impaired HNSCC overgrowth in vivo). Cal27 and FaDu both are BMI-1 positive HNSCC tumors (Fig. 6c).
In addition, regarding claims 3 and 4, “reduces metastasis of said cancer in said patient” (claim 3) or “reduces the number of BMI-1+ cancer stem cells” (claim 4) recited is merely intended result of the method steps positively recited. The court noted (quoting Minton v. Nat'/ Ass'n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a "'whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."' Id. Therefore, the result of claims 3 and 4 are given no weight. A “reduces metastasis of said cancer in said patient” or “reduces the number of BMI-1+ cancer stem cells” is expected with the method taught by Wang and Lin.
Regarding claim 10, “before, after or concurrently”, those are only three possible options for administering agent of (i) and agent of (ii) in combination. In addition, one of ordinary skill in the art would have known to develop an optimal administration regimen through routine methods.
Regarding claim 11, Lin teaches that blockade of PD-1/PD-L1 could reduce the population and activities of MDSCs and Tregs, and restore the cytotoxicity of T cells and NK cells, ultimately relieving the tumor immune escape and inhibiting tumor growth. (page 2, col. 1, para. 2). One of ordinary skill in the art would have expected that the combination taught by Wang and Lin (PTC-209 + pembrolizumab or nivolumab) would be able to reduce the immunosuppression and increasing anti-tumor T cell activities in a patient having a cancer (such as HNSCC).
Regarding claim 20, Wang teaches that PTC-209 administration significantly retarded and impaired HNSCC tumor (the elected species) growth in HNSCC xenograft model. Moreover, putative HNSCC CSCs marker CD44 revealed that the number of CD44-positive cells was much less in PTC-209 treated samples in relative to controls (Figs. 6a-6d, and § Pharmacological inhibition of Bmi1 by PTC-209 impaired HNSCC overgrowth in vivo). Wang teaches pharmacological targeting of BMI1 (e.g. administering PTC-209) resulted in impaired cell proliferation, migration and invasion, increase cellular apoptosis and reduced CSC subpopulation in HNSCC (also see, page 11, col. 1, para. 2). One of ordinary skill in the art would have expected that the combination taught by Wang and Lin (PTC-209 + pembrolizumab or nivolumab) would be able to reduce the number of cancer stem cells in a cancer patient (e.g. HNSCC).
Claim 9 is alternatively rejected under 35 U.S.C. 103 as being unpatentable over Wang (Wang et al., Cancer Cell Int., (2017) 17: 107, Publication Date: 11/21/2017) in view of Lin (Lin et al., Frontiers in Oncology, Volume 8, Article 532, Publication Date: 11/21/2018), as applied to claims 1-6, 9-11 and 20 above, and further in view of Bolomsky (Bolomsky et al., 17th International Myeloma Workshop, September 12-15, 2019, FP-103).
Wang and Lin teach method of claim 9, wherein said BMI-1 inhibitor is PTC209, as set forth above. However, Wang and Lin do not teach PTC596 (the elected species).
Bolomsky teaches that PTC596 can decrease BMI-1 protein level within 24h of treatment and demonstrated potent activity in parental and PI-resistant HMCLs. IC50 for PTC596 (median IC50 57nM) is > 10-fold reduced compared to the previously reported BMI-1 inhibitor PTC-209 (median IC50 680nM). The reduction of BMI-1 protein level significantly correlated with IC50s (page e113).
Bolomsky teaches that PTC596 shows remarkable activity in vivo in dose dependent fashion (page e114).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a BMI-1 inhibitor (such as PTC-209) in combination with an anti-PD-1 antibody (such as pembrolizumab or nivolumab) for treating a cancer (such as HNSCC) as taught by Wang and Lin, and to substitute PTC-209 with PTC596 (the elected species) in the combination, because Bolomsky teaches that PTC596 is a new BMI-1 inhibitor and PTC596 is more powerful and efficient than PTC-209 and PTC596 is suitable for clinical use. One of ordinary skill in the art would have a reasonable expectation that the PTC596 could be more efficient at a lower dosage when used in combination with anti-PD1 antibody. The motivation would have been to develop a more efficient combination therapy for cancers (such as HNSCC) and to expand the options for the combination treatment.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642