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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/17/2026 has been entered.
Response to Amendment
Acknowledgment is made of the amendment filed on 02/27/2026.
Election/Restriction
Applicant elected without traverse of invention Group I, and species :1) colorectal cancer; 2) anti-PD-1 antibody as species of immunotherapy agent, filed on 07/24/2024. Applicant did not elect any specific anti-PD-1 antibody in the reply filed on 07/24/2024.
Status of Claims
Claims 1, 6, 12, 18, 20 and 27 are pending and under examination in this office action.
Claims 12 is withdrawn.
Claims 1, 6, 18, 20 and 27 are under examination in this office action.
Action Summary/Response to Arguments
Applicant’s remarks on 02/27/2026 filed have been fully considered, but not persuasive to overcome Scope of Enablement rejection under 35 USC 112(a) and rejections under 35 USC 103 as being unpatentable over: 1) Culler in view of Lin; 2) Seeram in view of Chowdhury and Lin; 3) Rinsch ‘753 (US 2016/0000753) in view of Norden and Topalian; 4) Sing (US 2019/0328703) in view of Norden and Topalian, and rejections on the ground of non-statutory double patenting over US patent Nos.10792276 B2 and 11426380 B2. Applicant’s argument against individual reference on the record, motivation to combine, reasonable expectation of success and alleged unexpected result are addressed accordingly.
Priority
The instant application 17/284,363 filed on 04/09/2021 is a 371 of PCT/EP20/73436 filed 08/20/2020 and claims benefit of United Kingdom GB 1912107.8 filed 08/22/2019.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of foreign Application No. GB 1912107.8 is filed on April 9, 2021.
Information Disclosure Statement
The information disclosure statement dated 02/17/2026 is in compliance with the provisions of 37 CFR1.97. Accordingly, the reference listed in IDS are being considered by the Examiner.
Specification
The specification is objected to as failing to provide proper support for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o).
Claim 20 recite the anti-PD-1 immunotherapy treatment is an anti-PD-1 antibody selected from pembrolizumab, nivolumab, cemiplimab and pidilizumab.
Instant specification disclosed assay with urolithin A (UA) in combination with an anti-PD1 antibody (Example 4, Figure 8), wherein the activity of urolithin A seems be more potent than the anti-PD1 antibody in Figure 8. Example 4 / Figure 8 did not disclose which specific anti-PD1 antibody drug was used in combination with UA. The amended specification filed on 02/17/2026 describes the anti-PD1 antibody is a diagnostic anti-mouse PD-1 which is NOT anti-PD1 antibody recited in claim 20. As such, instant specification fails to provide sufficient support for the specific combinations of urolithin A with anti-PD-1 antibody recited in claim 20.
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.
Claim 1, 6, 18, 20 and 27 are rejected under 35 U.S.C. 112(a) first paragraph, as failing to comply with the enablement requirement, because the specification, while might be enabling for a method of treating colorectal cancer with a specific combination comprising urolithin A and one specific anti-PD-1 antibody as described in the amended specification filed 02/17/2026, does not reasonably provide enablement for treating colorectal cancer with combination genus comprising urolithin A with any anti-PD-1 antibody, especially for treatment of microsatellite instability high (MSI-H) colorectal cancer or mismatch repair deficient (dMMR) colorectal cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims to treating colorectal cancer with any combination comprising urolithin A and any anti-PD-1 antibody. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Independent claim 1 is amended to recite a method of treating disease state associated with inhibition of T cell activation with combination of a urolithin and an immunotherapy treatment, wherein the disease state is colorectal cancer and the immunotherapy treatment is anti-PD-1 antibody. Instant claims do not recite any dosage regimen for urolithin A and anti-PD-1 antibody. Claim 1 is construed under BRI as treating colorectal cancer with any combination comprising urolithin A combined with any anti-PD-1 antibody that have different structure, different activity/properties, different PK/PD profile and different interactions with different agents, etc.
Instant specification disclosed assay with urolithin A (UA) which reduces lesion incidence and size, and increases the infiltration of T cytotoxic cells inside tumors in a mouse model of colorectal cancer (AOM model) ( Examples 1-2, Figures 4-7 ). Instant specification also disclosed assay with urolithin A (UA) in combination with anti-PD1 immunotherapy (Example 4, Figure 8). However, Example 4 / Figure 8 at the time of filing did not disclose which specific anti-PD1 antibody drug is used in combination with UA, nivolumab (Opdivo), or pembrolizumab (Keytruda), or any other anti-PD1 antibody. Example 4 does not disclose the tested colorectal cancer (AOM model) are microsatellite instability high (MSI-H) colorectal cancer or mismatch repair deficient (dMMR) colorectal cancer.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
It is well known in the prior art that tumor/cancer treatment is highly unpredictable. “Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. ….This heterogeneity might result in a non-uniform distribution of genetically distinct tumor-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity).”(Dagogo-Jack, Nature Reviews Clinical Oncology, Volume 15, pages 81–94 (2018), published online Nov 8, 2017, Abstract, page 81).
Regarding immunotherapy in cancer treatment, different anti-PD1 antibody has different structure and activity. Chowdhury (J Intern Med, 2018; 283: 110–120) states: “Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy”(See page 110, left column).
Regarding the treatment of colorectal cancer, Oliveira (2019) teaches most CRC patients are not responsive to immunotherapy. Several factors may be involved in this lack of sensitivity, lack of T-cell infiltration, type 1 T-helper cell activity and low immune cytotoxicity in tumor microenvironment are thought to be involved (See abstract, page 3, left column, para 2).
Regarding treatment for microsatellite instability high (MSI-H) colorectal cancer or mismatch repair deficient (dMMR) colorectal cancer, Lee (2016, Immunotherapy, 8: 1-3, DOI: 10.2217/imt.15.97) teaches efficacy of PD-1 blockade in tumors with MMR deficiency. Lee teaches pembrolizumab activity in mismatch repair deficient CRC: “The response rate in the MMR proficient CRC cohort was 0% (0/25) with a disease control rate of 16%. In contrast, the MMR deficient CRC and noncolon cancer cohorts had response rates of 62% (8/13) and 60% (6/10), respectively, and disease control rates of 92 and 70%. CD8+ T cell infiltration and PD-L1 expression were more pronounced in the MMR deficient cohorts but did not independently correlate with response to therapy. Mutation associated neoantigens and mutational load correlated with improved progression free survival. This suggested that the higher antigenic load increased the probability of the presentation of an immunogenic antigen; however, a large number of mutations does not guarantee a response” (See page 2).
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
Instant speciation at the time of filing only disclosed one working example of combination comprising urolithin A (UA) and one non-identified anti PD-1 antibody on AOM model of colorectal cancer. NO combination comprising anti-PD-1 antibody selected from pembrolizumab, nivolumab, cemiplimab and pidilizumab as recited in claim 20 were evaluated in instant specification. The combination of urolithin A (UA) and anti-CD8 in instant Example 3 exhibits lower activity compared with control +anti-CD8, indicating that not any combination of urolithin A (UA) and immunotherapy would have beneficial effect of combination therapy. There is no working example or data in the specification to provide a nexus between those examples to practice the claimed method of treating colorectal cancer (e.g. MSI-H) with any combination of urolithin and any anti-PD-1 antibody in its full scope.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to develop administration protocols for practicing instantly claimed method of treating colorectal cancer (e.g. MSI-H) with combination of urolithin A and any anti-PD-1 antibody in its full scope. Working examples would be needed to determine the therapeutically effective dose for different combination of urolithin and anti-PD-1 antibody. The therapeutically effective amount may vary depending on many factors, such as the subjects being treated, the disease condition and intended result etc. Instantly claimed combination requires extensive experiment regarding the agent(s) selected, the amount and ratio thereof, the dosing regimen to be followed and administration route, etc.
Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention for treating colorectal cancer (e.g. MSI-H) with combination genus in full scope.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method of treating colorectal cancer with any combination comprising urolithin A and any anti-PD-1 antibody in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
Applicant argues “ in vivo experiments with UA and the anti-PD-I antibody are sufficiently representative of the now-claimed method... Although the anti-PD-I antibody is a diagnostic antibody, a person of ordinary skill in the art would reasonably extrapolate that other anti-PD-1 antibodies, which are also PD-1 antagonists, would be effective, when combined with UA, to reduce tumor volume”
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. Please note this 112(a) rejection is scope of enablement. Different anti-PD-1 antibodies have different structure, property, different activity and different interaction with urolithin. Due to high unpredictability of cancer treatment as elaborated above, POSA would NOT extrapolate any anti-PD-1 antibody exhibit the same activity when combined with UA .
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 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 non-obviousness.
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 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, 18, 20 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Culler et al. (WO 2019178542 A1), in view of Lin et al. (Digestion 2019;100:72–78, published online: October 17, 2018 , DOI: 10.1159/000494052, “Role of Gut Microbiota in the Development and Treatment of Colorectal Cancer”).
Culler teaches method of treating variety of cancer (e.g. colon cancer, lung cancer, etc.) comprising administering combination of immune checkpoint blockade immunotherapy and formulation comprising benzo-coumarin or dibenzo-pyrone(e.g. urolithin A), metabolized or synthesized from ellagic acid or derivative by non-pathogenic microbial cocktail (See abstract, page 3, lines 15-32; page 4, lines 8-10; page 22, lines 10-17; Figure 1-34; claims 1-31). Culler teaches embodiments comprising urolithin A (benzo-coumarin or dibenzo-pyrone), and an inhibitor of an inhibitory immune checkpoint molecule and/or a stimulatory immune checkpoint molecule, or any composition for use in checkpoint blockade immunotherapy (See page 29, lines 25-30; page 30, lines 1-2; claim 27). Culler teaches tumor treatment wherein urolithin A is administered alone via oral gavage without microbe cocktails, with and without anti-CTLA4, anti-PD1 or anti-PD-L1 therapy and tumor growth and tumor-specific T cell responses are compared among different treatment groups ( See page 69, lines 16-20; page 217, lines 19-20, lines 33-34; Figure 3, 6, 7 ). Culler explicitly teaches mice treated with urolithin A , and urolithin A combination with anti-CTLA4 had reduced tumor growth (e.g. CT26 colon cancer cell) compared with vehicle (See Figure 3, 6 and 7).
Culler teaches checkpoint blockade immunotherapy targets including anti-programmed cell death 1/PD-1 and PD-1 antagonist(e.g. PD-1 monoclonal antibody, e.g. pembrolizumab or KEYTRUDA®, nivolumab or OPDIVO®, BMS-936559, etc.) (See page 13, lines 3; page 30, lines 10-30; claim 14). Culler explicitly teaches mice treated with anti-PD1 monotherapy or combination of anti-PD1 with microbe mix had reduced tumor growth (e.g. colon cancer cell) compared with vehicle (See Fig. 29, 40).
Regarding claim 18, Culler teaches methods of treating variety of cancer (e.g. colon cancer, lung cancer, etc.) comprise administering ellagic acid derivative (e.g. urolithin A), wherein urolithin A is delivered before administration of, simultaneously with, and/or after administration or delivery of the formulation comprising immune checkpoint blockage therapy (e.g. anti-CTLA4) (See claim 17; page 22, lines 12-25; Example 4, Figure 3, 6 and 7).
Culler collectively teaches methods of treating cancer (e.g. colon cancer ) comprise administering combination comprising urolithin A (separate and/or metabolized from ellagic acid derivative by microbe mix) and checkpoint blockade immunotherapy (e.g. anti-PD1 immunotherapy).
Culler is silent about biomarker limitations of instant claim 6. The biological activity against biomarker are the properties of Culler’s formulation which will naturally flow by practicing Culler’s method of treating cancer comprise administering to a subject in need thereof an effective amount of Culler’s formulation. As stated in MPEP 2112(I), a claim to something which is old does not become patentable upon the discovery of a new property. e.g., the 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.
Further, Lin teaches role of gut microbiota in the development and treatment of colorectal cancer. Lin teaches some pathogenic bacteria, e.g. Fusobacterium, related to colorectal cancer (CRC) development and pathogenicity and is abundant in tumor tissue in patients with MSI-H (microsatellite instability-high) and CIMP-H (CpG island methylator phenotype-high) mismatch repair deficient colorectal cancer( See page 73, left column). Lin teaches intestinal microbes play important role in systemic immune responses and regulation of patients’ immune system through microbiota is one of the key mechanisms of tumor immunotherapy(See page 75, right column). Lin teaches “cancers with defective gene mismatch repair respond to PD-1 inhibitors well. CRC patients with chromosomal defect repair have a control with 62% rate of PD-1 inhibitors, compared with 16% of patients with complete chromosomal mismatch repair ..provide ideas for the use of gut microbiota in cancer treatment, that regulating the composition of gut flora may enhance the efficacy of cancer immunotherapy and lay the foundation of treatment of CRC patients with defects in mismatch repair.” (See page 76, left column).
Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Culler and Lin. It would have been obvious to one of ordinary skill in the art before the effective filing date of instant invention to further explore the combination therapy comprising urolithin A (separate or metabolized from ellagic acid derivative by microbe mix) and checkpoint blockade immunotherapy (e.g. anti-PD1 immunotherapy/ anti-PD1 antibody) taught by Culler for treating colorectal cancer CRC based on the combined beneficial teaching of Culler and Lin, and test for biomarkers in need thereof. A skilled artisan would be motivated to exploring treating colorectal cancer because colorectal cancer is a broader term encompassing colon cancer. Based on the complementary anticancer mechanisms of urolithin A and anti-PD immunotherapy, further exploration of Culler combination therapy would provide an alternative combination therapy that might benefit colorectal cancer patient with chromosomal defect repair as suggested by Lin.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of urolithin and immunotherapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that cited art does not disclose or suggest a method of treating a disease state associated with inhibition of T-cell activation comprising urolithin A and anti-PD1 antibody...one of ordinary skill in the art would not have had a reasonable expectation of success in developing the now- claimed invention(Remarks, page 8).
Response: Colon cancer and colorectal cancer are closely related conditions wherein colorectal cancer is a broader term encompassing both colon and rectal cancer. Culler collectively teaches method of treating cancer (e.g. colon cancer) comprising administering formulation comprising urolithin A (separate or metabolized from ellagic acid derivative by gut microbe mix) and checkpoint blockade immunotherapy (e.g. anti-PD1 immunotherapy), wherein gut microbiota improves the efficacy of cancer immunotherapy . Culler also teaches pembrolizumab (Keytruda®) and nivolumab (Opdivo®) are commonly known anti PD-1 antibody that might be combined with formulation comprising urolithin A. Lin explicitly teaches colorectal cancer CRC patients with chromosomal defect repair (mismatch repair deficiency ) might benefit from enhanced efficacy of cancer immunotherapy by gut flora which is associated with biosynthesizing/metabolizing urolithins. Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Culler and Lin. A skilled artisan would be motivated to further explore the combination therapy comprising urolithin A (separate or metabolized from ellagic acid derivative by microbe mix) and checkpoint blockade immunotherapy (e.g. anti-PD1 immunotherapy) taught by Culler for treating colorectal cancer based on the beneficial teachings of Culler and Lin with reasonable expectation of success because colorectal cancer is a broader term encompassing colon cancer.
As MPEP 2143.02.I. stated : “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
Applicant argues Culler Figure 29 do not indicate a synergistic effect at least because the anti-PD-I antibody ( with vehicle) appears to reduce tumor growth better than or similarly to the combination of microbe mix 4, ellagic acid, and anti-PD-I therapy (Remarks, page 8).
Response: Please note the expectation of success need only be reasonable, not absolute. The combination of microbe mix 4, ellagic acid, and anti-PD-1 therapy might be similar to anti-PD1 monotherapy due to variety of factors, e.g. different type and/or amount of anti-PD-1, different amount of urolithin A metabolized/synthesized from ellagic acid or the interaction of anti-PD-1 with the microbe mix/ ellagic acid, etc. Culler teaches mice treated with anti-PD1 monotherapy or combination of anti-PD1 with microbe mix had reduced tumor growth (e.g. colon cancer cell) compared with vehicle in Figure 29.
Culler explicitly teaches mice treated with urolithin A, and urolithin A combination with anti-CTLA4 had reduced tumor growth (e.g. CT26 colon cancer cell) compared with vehicle (See Figure 3, 6 and 7). An ordinary skilled in the art would reasonably expect the combination of urolithin A with anti-PD-1 exhibit enhanced activity in reducing tumor growth based on Culler’s result and the complementary anticancer mechanisms of urolithin A and anti-PD immunotherapy.
Applicant argues about unexpected synergistic effect in Example 4/ Figure 8, “the improved effects related to tumor growth inhibition could not have been predicted based on the cited art (See Remarks, page 9).Response: Applicant’s argument about alleged synergistic effect /unexpected result is fully considered, but NOT persuasive. Instant disclosed efficacy in Example 4 is considered as additive effect of urolithin A and anti-PD1 antibody. Culler teaches mice treated with urolithin A, and urolithin A combination with anti-CTLA4 had reduced tumor growth (e.g. CT26 colon cancer cell) compared with vehicle (See Figure 3, 6 and 7). Culler teaches mice treated with anti-PD1 monotherapy or combination of anti-PD1 with microbe mix had reduced tumor growth (e.g. colon cancer cell) compared with vehicle (See Figure 29). Lin also teaches CRC patients with chromosomal defect repair (mismatch repair deficiency ) might benefit from enhanced efficacy of cancer immunotherapy by gut flora which is associated with biosynthesis/metabolite urolithins. The observed enhancement/improvement would not be unexpected based on the complementary anticancer mechanisms of urolithin A and anti-PD immunotherapy.
As stated in MPEP 716.02(d): “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)”. Instant claims are directed to a method of treating colorectal cancer with combination genus comprising urolithin A combined with any anti-PD-1 antibody. Instant claims do no recite any dosage regimen for urolithin A and the anti PD-1 antibody. Applicant’s alleged unexpected result of one embodiment comprising urolithin A and one unspecified anti-PD-1 antibody does not commensurate with instantly claimed scope of treating colorectal cancer with vast variety of combinations.
Claims 1, 6, 18, 20 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Seeram et al.(US 20090326057 A1, Applicant’s IDS dated 07/24/2024, Citation # AE1), in view of Chowdhury et al. (J Intern Med, 2018; 283: 110–120. doi: 10.1111/joim.12708, “Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy”) and Lin et al. (Digestion 2019;100:72–78, published online: October 17, 2018 , DOI: 10.1159/000494052, “Role of Gut Microbiota in the Development and Treatment of Colorectal Cancer”).
Regarding urolithin in cancer treatment, Seeram discloses method of treating neoplastic /hyperproliferative disease (e.g. cancer) with urolithins, elagitannin metabolites (See abstract, [0035], claims 1-12). Seeram discloses structure of urolithins A, B, etc. and teaches a method of treating cancer (e.g. colon cancer) with urolithin selected from the group consisting of urolithin A, urolithin B, and derivatives thereof, in mammal(e.g. human) (See abstract, Figure 1, Table 2, [0127]-[0129], Example 2, claims 1, 7-9).
Seeram teaches anti-proliferative activity of urolithins against a human colon cancer cell line HCT-116 (See Example 2, [0010], Fig. 3 ), and method of treating cancer wherein solid tumor is colon cancer(See Figure 3, [0014], Example 2, claim 4).
Regarding limitation of urolithin A , Seeram teaches urolithin A (UA) was rapidly absorbed and taken up in prostate gland, small intestine and colon(See [0127] and explicitly teaches urolithin A (UA)/UA-conjugates that concentrated in the mouse prostate had antiproliferative activity against human androgen sensitive and insensitive CaB cell lines (See Example 4, [0131]).
Seeram teaches combined use of urolithins and other anticancer agents has advantages of lower dosage and complementary effect of different drugs (See [0048]).
Seeram is silent about the biomarker limitations of instant claim 6. The biological activity against biomarker are the properties of urolithins which will naturally flow by practicing Seeram’s method of treating cancer comprise administering to a subject in need thereof an effective amount of urolithin. A skilled artisan would have known to treat cancers with urolithins and test for biomarkers in need thereof. Further, as elaborated in proceeding 103 rejection and applied as before, Lin teaches cancers with defective gene mismatch repair (e.g. CRC) might respond to PD-1 blockade immunotherapy.
Seeram is silent about combining urolithins with immunotherapy for cancer treatment. However, combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment.
Chowdhury teaches combination therapy strategies for improving PD-1 blockade efficacy in cancer immunotherapy. Chowdhury teaches “ programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects” (See page 110, Fig. 1).
Chowdhury teaches PD-1 blockade agents (monoclonal antibodies of PD-1 e.g. nivolumab/Opdivo®, etc. ) in clinical trials (See page 111, right column, Table 1) and strategy to improve PD-1 blockade efficacy through combination therapy with other anticancer agent/treatment, such as chemotherapy, small molecules, cancer vaccines and immune-stimulatory agents, etc., wherein guiding principle for most combination therapies is to boost the efficacy of PD-1 blockade, either by improving tumor antigen presentation or rescuing dysfunctional immune effector cells (page 113, left column, Table 2). Chowdhury teaches combination therapy comprising anti-PD-1 antibody(e.g. pembrolizumab, nivolumab) (See Table 2).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." Jn re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Chowdhury. It would have been obvious to one of ordinary skill in the art before the effective filing date of instant invention to explore combination therapy comprising urolithins taught by Seeram and combination therapy comprising anti-PD-1 antibodies taught by Chowdhury, together with experimentation/ optimization based on the general knowledge of urolithins and cancer immunotherapy and arrive at instant claimed invention with reasonable expectation of success. A person of ordinary skill in the art would have known that urolithins could be used for treating cancer(e.g. colon cancer) and could be combined with other anticancer agent as taught by Seeram. It was also known that anti-PD-1 antibodies as an immune check point inhibitor/tumor immunotherapy agent could be used in combination with other pharmaceutical active agents for treating cancer as taught by Chowdhury.
A person of ordinary skill in the art would be motivated to combine the teaching of Seeram and Chowdhury because both teachings are directed to cancer treatment, and Chowdhury specifically teaches combination immunotherapy comprising anti-PD-1 antibodies for improved efficacy of immunotherapy. Lin also teaches cancers with defective gene mismatch repair (e.g. CRC) might respond to PD-1 blockade immunotherapy. The combined teaching of prior art, together with general knowledge of urolithins and immunotherapy would provide an alternative combination therapy comprising urolithins and immunotherapy (anti-PD-1 antibody) for cancer treatment(e.g. colon/colorectal cancer) with potential improved efficacy.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of urolithin, combination immunotherapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that “cited art does not disclose or suggest a method of treating a disease state associated with inhibition of T-cell activation… has not provided any specific rationale for why a person of ordinary skill in the art would combine urolithin (as disclosed by Seeram) with an anti-PD-1 antibody (as disclosed by Chowdhury) as opposed to any other possible cancer treatment. Importantly, Chowdhury discloses at least 20 possible combination therapies but does not mention urolithins. Therefore, the selection of a urolithin and immunotherapy can only be based on hindsight. Moreover, based on the cited combination of references one of ordinary skill in the art would not have had a reasonable expectation of success in developing the now-claimed invention” (Remarks, page 9-10).
Response: Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Chowdhury. Applicant’s argument about Chowdhury is NOT persuasive. Combination therapy comprising urolithins and anti-PD-1 antibody are based on the combined beneficial teachings of Seeram and Chowdhury. Seeram teaches combined use of urolithins and other anticancer agents has advantages of lower dosage and complementary effect of different drugs. Anti-PD-1 antibody (e.g. pembrolizumab, nivolumab ) are well-known immunotherapy agent. A skilled artisan would be motivated to explore urolithins taught by Seeram with combination therapy comprising anti-PD-1 antibody taught by Chowdhury, and expect the new combination therapy comprising urolithins and anti-PD-1 antibody provide enhanced efficacy based on complementary mechanisms, and benefit of lower dosing regimen for anti-PD-1 antibody in cancer treatment.
Applicant also argues about unexpected synergistic effect in Example 4/ Figure 8, “the improved effects related to tumor growth inhibition could not have been predicted based on the cited art which is similar to preceding 35 USC 103 rejection.
Response: A skilled artisan would reasonably expect enhancement/improvement of combination therapy based on the complementary anticancer mechanisms of urolithin A taught by Seeram and anti-PD-1 antibody taught by Chowdhury. Further, as elaborated in preceding response in preceding 103 rejection, instant disclosed efficacy of one embodiment comprising urolithin A and one unspecified anti-PD-1 antibody is considered as additive effect, and does not commensurate with instantly claimed scope of treating colorectal cancer with vast variety of combinations in absence of sufficient support by instant specificaton.
Claims 1, 6, 18, 20 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Seeram et al.(US 20090326057 A1, Applicant’s IDS dated 07/24/2024, Citation # AE1), in view of Oliveira et al. (Frontiers in Oncology, 2019 May 14; 9:396. doi: 10.3389/fonc.2019.00396, Review of PD-1/PD-L1 Inhibitors in Metastatic dMMR/MSI-H Colorectal Cancer).
The collective teachings of Seeram is elaborated in preceding 103 rejection and applied as before
Seeram teaches combined use of urolithins and other anticancer agents has advantages of lower dosage and complementary effect of different drugs.
Seeram is silent about combining urolithins with immunotherapy for cancer treatment. Seeram is silent about the biomarker limitations of instant claim 6.
Oliveira reviews therapy for metastatic colorectal cancer (CRC) with PD-1 and PD-1 inhibitor, alone or in combination with other therapies (immunotherapy, targeted therapy and chemotherapy) (See whole article). Oliveira teaches clinical trial results of anti-PD-1 antibody, e.g. pembrolizumab, nivolumab, alone or in combination with other anti-tumor agent in treating microsatellite-instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (See Tables 1-3, page 3 and 4). Oliveira teaches the efficacy of pembrolizumab in treating patients with dMMR mCRC lead to the approval of the first ever agnostic (i.e., histology and tumor-site independent) cancer drug in US (See page 3, left column).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." Jn re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Oliveira. It would have been obvious to one of ordinary skill in the art before the effective filing date of instant invention to explore combination therapy comprising urolithins taught by Seeram and combination therapy comprising anti-PD-1 antibodies taught by Oliveira, together with experimentation/ optimization based on the general knowledge of urolithins and cancer immunotherapy and arrive at instant claimed invention with reasonable expectation of success. A person of ordinary skill in the art would have known that urolithins could be used for treating cancer(e.g. colon cancer) and could be combined with other anticancer agent as taught by Seeram. It was also known that anti-PD-1 antibodies (e.g. pembrolizumab, nivolumab) could be used in combination with other pharmaceutical active agents for treating (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer as taught by Oliveira.
A person of ordinary skill in the art would be motivated to combine the teaching of Seeram and Oliveira because both teachings are directed to cancer treatment, and Oliveira teaches combination immunotherapy comprising anti-PD-1 antibodies for improved efficacy of immunotherapy. The combined teaching of prior art, together with general knowledge of urolithins and immunotherapy would provide an alternative combination therapy comprising urolithins and immunotherapy (anti-PD-1 antibody) for cancer treatment(e.g. colon/colorectal cancer) with potential improved efficacy.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of urolithin, combination immunotherapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1, 6, 18, 20 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Rinsch et al.( US 2016/0000753 A1, hereafter “Rinsch’ 753”, corresponding to US 9,962,366 B2), in view of Norden et al. (Carcinogenesis, 2019, Vol. 40, No. 1, 93–101, Advance Access publication November 12, 2018, doi:10.1093/carcin/bgy158, “Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells”) and Topalian et al.(New England Journal of Medicine, 2012, 366:2443-54, "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer").
Claim Interpretation: Instant claim 20 recite anti-PD-1 antibody selected from pembrolizumab, nivolumab, cemiplimab and pidilizumab. As disclosed by instant Specification (See PGPub US 2021/0346342 A1 [0087]), nivolumab is also known as BMS-936558, evidenced by PubChem (retrieved from https://pubchem.ncbi.nlm.nih.gov/substance/178103907).
Rinsch’ 753 discloses urolithins are ellagitannin- and ellagic acid-derived metabolites produced, e.g., by mammalian colonic microflora, including human colonic microflora which increase autophagy and promote longevity (See abstract, [0005]-[0010]). Rinsch’ 753 discloses “autophagy is a lysosomal degradation pathway in both animals and plants that is essential for development, differentiation, homeostasis, and survival. In animals, autophagy serves principally as an adaptive mechanism to protect organisms against diverse pathologies, including infection, cancer, neurodegeneration, heart disease, and aging” (See [0002]).
Rinsch’ 753 discloses benefit of increasing autophagy including improved immune response ( See Table 1) and clinical use for treating variety of disease (e. g. cancer, immune disorders, etc.), wherein increasing autophagy and/or improving mitochondrial function are desirable(See [0335]). Rinsch’ 753 discloses method of treating cancer, comprising administering a therapeutically effective amount of a compound selected from the group consisting of urolithin A, urolithin B, etc.( See [1495]).
Regarding urolithin A, Rinsch’ 753 teaches urolithin A induce autophagy in a variety of cells, wherein increasing concentrations of urolithin A resulted in increasing levels of phosphorylated AMPKa (See Examples 9-14).
Rinsch’ 753 collectively teaches treating cancer with urolithins (e. g. urolithin A ) which can increase autophagy in cells, improve mitochondrial function and immune response.
Rinsch’ 753 does not explicitly teach treating colorectal cancer with urolithins. However, Rinsch’ 753 teaches urolithins are metabolites produced by mammalian /human colonic microflora , and urolithin A (two hydroxyls) and B ( one hydroxyl) exist in distal parts of the colon (See FIG. 3; [1023]), and method of treating cancer with urolithins. It would be logical and obvious for a skilled artisan to explore treating colorectal/colon cancer with urolithins.
Rinsch’ 753 is silent about the biomarker limitations of instant claim 6. The biological activities against biomarkers are the properties of urolithins which will naturally flow by practicing Rinsch’ 753 method of treating cancer comprise administering to a subject in need thereof an effective amount of urolithin.
Further, Norden teaches urolithin A gains antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in HCT 116 colon cancer cells(See abstract, Figures 1-3). Norden teaches urolithin A also affect a number of cellular signaling pathways, including autophagic signaling, that could also contribute to the growth inhibition of colon cancer cells( See page 99, right column). Gonzalez-Sarrıas(2016) incorporated by Norden further teaches effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved, indicating potential combination therapy comprising urolithins for treating colorectal cancer. Norden teaches combination therapy comprising urolithin A and other anticancer agent(oxaliplatin) exhibiting synergism with combinatorial indices <1 (See page 95, right column; Table 1).
Topalian teaches blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance and teaches method of immunotherapy treatment for a variety of cancer (e.g. colorectal cancer, melanoma, lung cancer, etc.) with anti–PD-1 antibody(e.g. BMS-936558) (See Abstract, Methods). Topalian teaches dose-escalation study of anti–PD-1 monoclonal antibody BMS-936558 (AKA, nivolumab, MDX-1106, ONO-4538) in clinical trial NCT00730639 for patients with variety of cancers including colorectal cancer (See Abstract, page 2444, left column; Methods/Results , Tables 1-2). Topalian teaches “programmed death 1 (PD-1) is a key immune checkpoint receptor expressed by activated T cells, and it mediates immunosuppression. PD-1 functions primarily in peripheral tissues, where T cells may encounter the immunosuppressive PD-1 ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed by tumor cells, stromal cells, or both. Inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity” (See page 2444, left column).
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." Jn re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Norden. It would have been obvious to one of ordinary skilled in the art before the effective filing date of instant invention to explore combination therapy comprising urolithins taught by Rinsch’ 753 and Norden, and immunotherapy comprising anti-PD-1 antibodies taught by Topalian, together with experimentation and optimization based on the general knowledge of urolithins and cancer immunotherapy and arrive at instant claimed invention with reasonable expectation of success. A person of ordinary skill in the art would have known that urolithins increase autophagy and immune response and could be used for treating cancer(e.g. colon cancer) as taught by Rinsch’ 753, and could be combined with other anticancer agent as taught by Norden, It was also known that anti-PD-1 antibodies (e.g. BMS-936558/ nivolumab) as an immune check point inhibitor/tumor immunotherapy agent could be used for treating a variety of cancer (e.g. colorectal cancer, melanoma, lung cancer, etc.) as taught by Topalian.
A person of ordinary skill in the art would be motivated to combine the teaching of prior art because Pan teaches autophagy in immunotherapy and optimal combination of autophagy-based inducer with various therapeutic strategies may represent an important approach by eliciting immunogenic cell death in cancer treatment. Rinsch’ 753 explicitly teaches urolithins increase autophagy/immune response and use in cancer treatment. The combined teachings of prior art, together with general knowledge of urolithins and immunotherapy would provide an alternative combination therapy comprising urolithins and immunotherapy for cancer treatment(e.g. colon/colorectal cancer) with potential improved efficacy.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of urolithin, combination immunotherapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that “cited art does not disclose or suggest a method of treating a disease state associated with inhibition of T-cell activation… has not provided any specific rationale for why a person of ordinary skill in the art would replace the oxaliplatin (as disclosed by Norden) with an anti-PD-1 antibody (as disclosed by Topalian) as opposed to any other possible cancer treatment. Therefore, the selection of a urolithin and immunotherapy can only be based on hindsight. Moreover, based on the cited combination of references one of ordinary skill in the art would not have had a reasonable expectation of success in developing the now-claimed invention (Remarks, page 11).
Response: Applicant’s argument about Norden and Topalian are NOT persuasive. Combination therapy is common practice to enhance efficacy in medication especially for cancer treatment as illustrated by Norden. As elaborated in above rejection, combination therapy comprising urolithins and anti-PD-1 antibody are based on the combined beneficial teachings of Rinsch’ 753, Norden and Topalian. Rinsch’ 753 explicitly teaches urolithins increase autophagy/immune response and use in cancer treatment. Norden teaches combination therapy comprising urolithin A and other anticancer agent(oxaliplatin) exhibiting synergism for treating colon cancer, demonstrating that urolithins could be effectively used in combination therapy for treating colon cancer. BMS-936558 (i.e. nivolumab, Opdivo® ) is a well-known anti–PD-1 antibody for cancer treatment (including colorectal cancer) as taught by Topalian. A skilled artisan would be motivated to explore urolithins taught by Rinsch’ 753 in combination therapy with anti-PD-1 antibody (e.g. BMS-936558, nivolumab) taught by Topalian, and reasonably expect the new combination therapy comprising urolithins and anti-PD-1 antibody (e.g. BMS-936558, nivolumab) provide enhanced efficacy based on complementary mechanisms.
Applicant also argues about unexpected synergistic effect in Example 4/ Figure 8, “the improved effects related to tumor growth inhibition could not have been predicted based on the cited art (See Remarks, page 4), which is similar to preceding 35 USC 103 rejection.
Response: Please note instant specification did NOT disclose the specific anti–PD-1 antibody in combination with urolithin A in Example 4/Figure 8. Given the facts: 1) urolithins are known to exert immune-modulatory effects by Rinsch’ 753 ; 2) urolithins have been combined with other anticancer agents and exhibit synergy in cancer treatment as taught by Norden; 3). anti–PD-1 antibody (e.g.BMS-936558/ nivolumab) was used for treating a variety of cancer (e.g. colorectal cancer, etc.) as taught by Topalian. A POSA would have reasonable expectation that combination therapy comprising urolithins and anti-PD-1 antibody would yield improved results based on the complimentary anticancer mechanisms. As such, instant claimed improved efficacy is not unexpected. Further, as elaborated in preceding response in preceding 103 rejection, Applicant’s alleged unexpected result of one embodiment comprising urolithin A and one undefined/unspecified anti-PD-1 antibody does not commensurate with instantly claimed scope of treating colorectal cancer with vast variety of combinations.
Claims 1, 6, 18, 20 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Sing et al.( US 2019/0328703, hereafter “Sing’ 703”, corresponding to US 10,792,276 B2), in view of Norden et al. (Carcinogenesis, 2019, Vol. 40, No. 1, 93–101 “Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells”), and Topalian et al.(New England Journal of Medicine, 2012, 366:2443-54, "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer").
Sing’ 703 discloses urolithins (compound of Formula I ) boost immune function and health by improving immune cellular and antibody (humoral) responses (See abstract, [0015]-[0021]; Table 1 ). Sing’ 703 discloses urolithins (compound of Formula I) may be used as immune enhancers, increase the number and function of immune cells for cancer immunotherapy, including activated T-cells(See [0131]).
Regarding urolithin A, Sing’ 703 teaches structure of urolithin A and activities thereof in a variety of cells, e.g. stem cell, haematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) (See [0203]; Figures 2-6; Examples 3- 5).
Sing’ 703 does not explicitly teach treating colorectal cancer with urolithins. However, Sing’ 703 teaches urolithins are metabolites produced by mammalian /human gut/colonic microflora (See [0014]), and method of treating cancer/immunotherapy with urolithins. It would be logical and obvious for a skilled artisan to explore treating colorectal /colon cancer with urolithins.
Sing’ 703 is silent about the biomarker limitations of instant claim 6. The biological activity against biomarker are the properties of urolithins which will naturally flow by practicing Sing’ 703 method of treating cancer comprise administering to a subject in need thereof an effective amount of urolithin. A skilled artisan would have known to treat cancers with urolithins and test for biomarkers in need thereof.
Sing’ 703 is silent about combining urolithins with immunotherapy treatment.
The teachings of Norden and Topalian are elaborated in preceding 103 rejections and applied as before. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." Jn re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combination therapy is a common practice to enhance efficacy in medication especially for cancer treatment as taught by Norden. It would have been obvious to one of ordinary skilled in the art before the effective filing date of instant invention to explore combination therapy comprising urolithins taught by Sing’ 703 and Norden, and immunotherapy comprising anti-PD-1 antibodies taught by Topalian, together with experimentation and optimization based on the general knowledge of urolithins and cancer immunotherapy and arrive at instant claimed invention with reasonable expectation of success. A person of ordinary skill in the art would have known that urolithins could be used for raising immune response in cancer treatment (e.g. immunotherapy) as taught by Sing’ 703, and could be combined with other anticancer agent as taught by Norden, It was also known that anti-PD-1 antibodies as an immune check point inhibitor/tumor immunotherapy agent could be used for treating a variety of cancer (e.g. colorectal cancer, melanoma, lung cancer, etc.) as taught by Topalian.
A person of ordinary skill in the art would be motivated to combine the teaching of prior art because Sing’ 703 teaches urolithins maybe used as immune enhancers, increase the number and function of immune cells (e. g. T cell) for cancer immunotherapy. The combined teachings of prior art, together with general knowledge of urolithins and immunotherapy would provide an alternative combination therapy comprising urolithins and immunotherapy for cancer treatment(e.g. colorectal cancer) with potential improved efficacy.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of urolithin, combination immunotherapy in cancer treatment. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s argument is similar to argument presented in preceding 103 rejection over Rinsch ‘753 in view of Norden, and Topalian.
The examiner’s response is similar as preceding response presented in Rinsch ‘753 in view of Norden, and Topalian : Given the facts: 1) urolithins are known to exert immune-modulatory effects as taught by Sing’ 703; 2) urolithins have been combined with other anticancer agents and exhibit synergy in cancer treatment as taught by Norden; 3). anti–PD-1 antibody (e.g.BMS-936558/ nivolumab) was used for treating a variety of cancer (e.g. colorectal cancer, etc.) as taught by Topalian. A POSA would be motivated to explore combination therapy comprising urolithins and anti-PD-1 antibody, and have reasonable expectation that combination therapy comprising urolithins and anti-PD-1 antibody would yield improved results based on the complimentary anticancer mechanisms. As such, instant claimed improved efficacy is not unexpected. Further, as elaborated in preceding response in preceding 103 rejection, Applicant’s alleged unexpected result of one embodiment comprising urolithin A and one unspecified anti-PD-1 antibody does not commensurate with instantly claimed scope of treating colorectal cancer with vast variety of combinations.
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 1, 6, 18, 20 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7-13 of U.S. Patent No. 10,792,276 B2 in view of Topalian et al.(New England Journal of Medicine, 2012, 366:2443-54, "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer").
Reference claims are directed to a method of raising or enhancing immune response wherein the immune function or immune health of the subject is improved by administering compound of formula(I). Reference claim 7 refers to immunocompromised subject. Reference claims 8-9 refer to compound of formula I selected from urolithins A, B, C and D.
Reference claims are silent about combining urolithins (compound of formula I) with immunotherapy treatment for treating colorectal cancer. The collective teachings of Topalian is elaborated in preceding 103 rejections and applied as before.
It’s well-known that cancer patients are immunocompromised and immunotherapy is cancer treatment that enhances immune response to help the subject fight cancer. It would have been obvious to one of ordinary skilled in the art to explore combination therapy comprising urolithins that can improve immune function/immune health in immunocompromised subject taught by reference claims and immunotherapy comprising anti-PD-1 antibodies taught by Topalian, together with experimentation/ optimization based on general knowledge of urolithins and cancer immunotherapy and arrive at instant claims with reasonable expectation of success.
The instant application shares at least one common inventor and/or applicant with the reference patent. Further, the instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Claims 1, 6, 18, 20 and 27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 13-20 of U.S. Patent No. 11426380 B2 in view of Topalian et al.(New England Journal of Medicine, 2012, 366:2443-54, "Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer").
Reference claims are directed to a method of promoting stem cell regeneration, differentiation etc. by administering compound of formula(I)(urolithins). Reference claims 14-19 refer to compound of formula I selected from urolithins A, B, C and D.
Reference claims are silent about combining urolithins (compound of formula I) with immunotherapy treatment for treating colorectal cancer. The collective teachings of Topalian is elaborated in preceding 103 rejections and applied as before.
It’s well-known that stem cell regeneration, differentiation are associated with immunotherapy for cancer treatment. It would have been obvious to one of ordinary skilled in the art to explore combination therapy comprising urolithins that can promote stem cell regeneration/differentiation taught by reference claims and immunotherapy comprising anti-PD-1 antibodies taught by Topalian, together with experimentation/ optimization based on general knowledge of urolithins and cancer immunotherapy and arrive at instant claims with reasonable expectation of success.
The instant application shares at least one common inventor and applicant with the reference patent. Further, the instant application is not related to the reference patent, thus no 35 USC 121 shield exists.
Conclusion
No claims are allowed.
.
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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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