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 .
Election/Restrictions
Applicant’s election without traverse of group I in the reply filed on 7/13/26 is acknowledged.
Applicant further elected the species of the plurality of first cluster comprising a plurality of genes consisting of FAP, MMP2, CDH11, PRRX1, GAS1, ALPL, DLX5, and ZEB1, and the species of the second cluster comprising a plurality of genes consisting of INHBA, LOXL2, MMP14, WNT5A, TWIST2, ITGA5, PLAU and GREM1.
Claim 1 has been searched, commensurate in scope with the election to consider detecting a CAF subset differentially expressing “a plurality” of genes in the first elected set and/or “a plurality” of genes in the second elected set. Upon searching, the Puram reference was identified which teaches additional cluster 0 and cluster 3 genes, and so the search was expanded to include these, and these are REJOINED to the elected species. Specifically, any gene that is listed in instant claim 1 and Table S5 of Puram is rejoined to the elected combination.
Claim 9 has been examined to require at least (5) genes from the first and second elected and rejoined sets.
While the election of species refers to GREM1, TWIST2, MMP14 and WNT5A, these genes are recited in instant claim 1 as having an extra “1” at the end. As the recited genes “GREM11, TWIST21, and WNT5A1” do not appear to be known genes, the claims are indefinite. For the purposes of compact prosecution, the election and the claim have been examined for the species recited in the election of species paper.
Applicant is advised to review ALL genes recited in claims 1, both parts. A cursory review finds that many genes listed appear to have an extra “1” at the end, though it is not immediately apparent when a “1” in the final position if a gene name may be a mistake and may be intended. These genes do not appear to have known counterparts in public databases, such as genecards.org. As a courtesy, the examiner has noticed that at least the following non-elected genes appear to have problematic recitations of an extra “1” at the end of the gene recitation: VCAN1, Loxl11, MFAP21, MMP111, Adam121, Postn1, Tpm11, Tpm21, Serpinh11, Col3A11, col5a21, Col6a311, col5a11, Tnfrsf12a1, Col1a11, and GREM11. Any correction must have adequate basis in the original specification.
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.
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.
Claims 1 and 3-10 are 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.
The elected genes “MMP14, WNT5A and TWIST2” appear in part (a)(2) of claim 1 with an extra “1” at the end of the genes. This makes it indefinite if the claim intends to recite MMP14 or MMP141, for example. As MMP141, WNT5A1, and TWIST21 do not appear to be known genes (as queried at genecards.org and using google) the claims have been interpreted to recite the genes listed in the election, in the interest of compact prosecution. Correction and identification of basis for the correction is required.
The claims recite the relative terms “enrichment” and “differentially expressing” without giving any standard or basis for how to determine the relative feature. That is, it is unclear how much must be detected to be detecting “enrichment” or what the “differential” expression is relative to.
In claims 8 and 10, it is unclear which fibroblasts “the fibroblasts” refer to. The claim previous mentions a CAF subset but not “the fibroblasts in the tumor biopsy.”
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.
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.
Claim(s) 1, and 5-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Puram et al. (2017, Cell 171, 1611–1624) in view of Cramer et al. (Oral Oncology 99 (2019) 104460; pages 1-10).
Puram teaches a method comprising detecting in a tumor biopsy from a subject an enrichment of a CAF subset differentially expressing the Cluster-0 genes FAP and CDH11, see supplemental Table S5 which discloses that FAP and CDH11 are differentially expressed between CAF subsets, FAP and CDH11. See Table S5 which discloses that these genes are “CAF1” genes.
Regarding claim 9, the reference teaches at least 5 of the first and second cluster genes are CAF1 genes, meaning they are differentially expressed in the CAF1 subset.
These include from Cluster-0 at least: AEBP1, CLEC11A, CDH11, CTGF, and FAP, and from Cluster-3 at least: ANXA5, AQP1, LOXL2, WNT5A, TWIST2, ITGA5, PLAU, and GREM1.
Puram teaches that the tested tumors were from patients having head and neck squamous cell carcinoma, see p. e3, “Human Tumor Specimens”.
The reference teaches that a small fragment of a human tumor speciman was snap frozen for bulk whole exome sequencing and single-cell RNA-seq, see p. e3. Single-cell profiles of non-malignant cells highlighted the composition of the tumor microenvironment (TME, p. 1613).
The reference teaches that analysis partitioned cancer associated fibroblasts (CAF) into two types CAF1 and CAF2, and that the intra-tumoral CAF heterogeneity is consistent with the view that CAFs are involved in complex and structural paracrine interactions in the tumor microenvironment (p. 1614, first column, Table S5, Figures S2E). Further, the reference teaches that tumors with both high CAF scores and high p-EMT scores had a particularly high propensity for metastasis (Figure S7I and p. 1622).
Puram does not teach treating the subject with an immunotherapy.
Cramer teaches that recent clinical trials demonstrated improved outcome from the immune checkpoint inhibitors in HNSCC compared with the standard of care. The reference reports on a variety of clinical trials where immunotherapy, including anti-PD1 antibodies pembrolizumab and nivolumab improved one or more of overall survival and quality of life relative to standard of care therapy in HNSCC. The reference reports many instances of immunotherapy with anti-PD1-PD-L1 agents, throughout. The reference teaches that immunotherapy is rapidly altering the therapeutic landscape in HNSCC improving survival and reducing toxicity compared with established treatments (p. 8).
It would have been obvious before the effective filing date to have modified the method taught by Puram to have treated the HNSCC patients disclosed therein with immunotherapy, in particular anti-PD1 antibodies. One would have been motivated to do so to provide a way to ameliorate disease while improving survival and reducing toxicity compared to other established treatments.
About claims 5 and 10, figure S2D shows that the relative proportion of CAF1 and CAF2 subsets of all fibroblasts. Where the CAF are on the far left, and the figure describes that the CAF1 and 2 subpopulations are separated by 9 on the PC2 axis. The reference does not teach that at least 30% of the cells were CAF1. However, it would have been obvious to have treated all patients that have HNSCC, including those that have more than 30% CAF1 cells, in order to ameliorate disease. There is no disclosed criticality for that cutoff in the context of the instant claim.
7. Claim(s) 1, 3-4 and 6-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Puram et al. in view of Mei et al. (Cancer Medicine. 2020;9:640–652).
Puram teaches a method comprising detecting in a tumor biopsy from a subject an enrichment of a CAF subset differentially expressing the Cluster-0 genes FAP and CDH11, see supplemental Table S5 which discloses that FAP and CDH11 are differentially expressed between CAF subsets, FAP and CDH11. See Table S5 which discloses that these genes are “CAF1” genes.
Regarding claim 9, the reference teaches at least 5 of the first and second cluster genes are CAF1 genes, meaning they are differentially expressed in the CAF1 subset.
These include from Cluster-0 at least: AEBP1, CLEC11A, CDH11, CTGF, and FAP, and from Cluster-3 at least: ANXA5, AQP1, LOXL2, WNT5A, TWIST2, ITGA5, PLAU, and GREM1.
Puram teaches that the tested tumors were from patients having head and neck squamous cell carcinoma, see p. e3, “Human Tumor Specimens”.
The reference teaches that a small fragment of a human tumor specimen was snap frozen for bulk whole exome sequencing and single-cell RNA-seq, see p. e3. Single-cell profiles of non-malignant cells highlighted the composition of the tumor microenvironment (TME, p. 1613).
The reference teaches that analysis partitioned cancer associated fibroblasts (CAF) into two types CAF1 and CAF2, and that the intra-tumoral CAF heterogeneity is consistent with the view that CAFs are involved in complex and structural paracrine interactions in the tumor microenvironment (p. 1614, first column, Table S5, Figures S2E). Further, the reference teaches that tumors with both high CAF scores and high p-EMT scores had a particularly high propensity for metastasis (Figure S7I and p. 1622).
Puram does not teach treating the subject with an immunotherapy.
Mei teaches a fourth generation CAR-T cell therapy for the treatment of HNSCC, and demonstrate excellent preclinical studies for patients with HNSCC. It would have been obvious to have modified the method taught by Puram by treating patients with CAR-T cells to kill the cancer cells. One would have had a reasonable expectation of success because Mei demonstrates that the CAR-T cell they designed two different CAR-T cells that showed antitumor function in vitro and in vivo. See Abstract and throughout.
About claims 5 and 10, figure S2D shows that the relative proportion of CAF1 and CAF2 subsets of all fibroblasts. Where the CAF are on the far left, and the figure describes that the CAF1 and 2 subpopulations are separated by 9 on the PC2 axis. The reference does not teach that at least 30% of the cells were CAF1. However, it would have been obvious to have treated all patients that had HNSCC, including those that have more than 30% CAF1 cells, in order to ameliorate disease. There is no disclosed criticality for that cutoff in the context of the instant claim.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-16 of copending Application No. 18942140 in view of Brodsky, (April 16, 2016. 8 pages. Obtained from #AACR16 Update: The Promise of Synthetic Biology and CAR T Cell Technologies - Cancer Research Institute on 9/18/2026.).
The copending claims teach detecting differential expression of 3 to 80 genes set forth in the recited tables. Table 1A of the copending application recites CDH11, FAP, GREM1, INHBA, MMP2, PLAU and MMP14, and table 2B of the copending application recites GREM1, MMP14, MMP2, LOXL2, WNT5A, GAS1, TWIST2, and IHNBA. Table 2B of the copending application also recites at least rejoined genes AEBP1, COL6A3, and LUM, which completes the “at least 5” cluster-0 genes required by claim 9.
The copending application does not teach treating with immunotherapy.
However, Brodsky discusses the promise of immunotherapy for the treatment of cancer, mentioning treatment with anti-PD1 therapy as well as using CAR-T therapy in combination. The reference teaches that the approach is feasible and capable of achieving durable response in patients.
It would have been obvious to have modified the methods of the copending claims to treat the patients with immunotherapy as discussed by Brodsky. One would have been motivated to do so to provide a patient with a durable response for the amelioration of cancer.
This is a provisional nonstatutory double patenting rejection.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kieffer et al. (Cancer Discov 2020;10:1330–51) teaches specific clusters of CAF that are associated with immunosuppression and immunotherapy resistance. See Abstract and throughout.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
Prosecution Insights