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
Status of 17/904,677
Claims 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 are currently pending.
Priority
Instant application 17/904,677, filed 8/19/2022, claims priority as follows:
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Support for the instant claims is present in the provisional application, and thus, the instant claims are granted the effective filing date of 2/20/2020.
Information Disclosure Statement
All references from the IDS’s submitted on 9/6/2022 and 5/1/2025 have been considered unless marked with a strikethrough.
Response to Applicants Amendments/Arguments
The amendment filed 5/19/2026 has been entered. Claims 1, 3, 5, 6, 8, 9, 15, 18, 21, 23, and 24 have been amended. No claims have been cancelled and no claims have been added.
In the Non-Final dated 2/26/2026, the abstract was objected to for a minor informality. In response, Applicant has corrected the minor grammatical informality, which overcomes the objection. Thus, the objection is withdrawn.
The drawings were objected to in the Non-Final dated 2/26/2026. In response, Applicant has submitted replacement drawings. However, the document with replacement drawings appears to be the same figures as previously submitted and thus, the objection is not overcome. The objection is maintained.
Claims 3 and 18 were objected to in the Non-Final dated 2/26/2026 for minor grammatical informalities. In response, Applicant has amended the claims to recite, “programmed death-ligand 1”, which overcomes the objection. Thus, the objection is withdrawn.
In the Non-Final dated 2/26/2026, claims 1-3, 5-6, 9, 11-12, 14-18, 20-21, 24, and 26-27 were rejected under 35 U.S.C. 112(a). In response, Applicant has amended the instant claims to omit the limitation “analog”, which overcomes the rejection. Thus, the rejection is withdrawn.
Claims 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 were rejected under 35 U.S.C. 103 in the Non-Final dated 2/26/2026. In response, Applicant argues that the reference Clinical Trial NCT03334617 does not provide evidence of success, as it solely the protocol of the study and does not provide results. Applicants arguments have been considered, and are persuasive. Thus, the rejection has been overcome and withdrawn.
However, Applicant has provided additional arguments regarding the 103 rejection. The Examiner notes with respect to Applicant’s argument that a skilled person would not have been motivated to substitute Olaparib for castalagin, the Examiner has considered the arguments but does not find them persuasive. Though castalagin is more potent than Olaparib, increased potency in an in vitro IC50 assay does not always translate to guaranteed intended treatment, in this case treatment of cancer resistant to immunotherapy. Higher potency can sometimes lead to increased toxicity and detrimental side effects.
Additionally, Applicants arguments that the anti-tumor effects of castalagin reported in the present application are not mediated by PARP1 inhibition have also been considered, and are not persuasive. While the Examiner acknowledges that mechanistically, the instant specification discloses castalagin is hydrolyzed to an ellagic acid and castalin, and ellagic acid is then further converted into urolithins by the gut microbiome, which then treats a cancer resistant to immunotherapy, a skilled artisan cannot be certain that the treatment of cancer resistant to immunotherapy disclosed herein solely occurs by this mechanism. Stated differently, a skilled artisan cannot rule out that no treatment of the cancer resistant to immunotherapy occurred via the PARP1 mechanistic pathway.
Election/Restriction
Applicant’s election of castalagin as the single disclosed species of castalagin or analog thereof, PD-1 inhibitor as the single disclosed species of immune checkpoint inhibitor therapy to which the cancer is resistant, and lung cancer as the single disclosed disease to treat in the reply filed 9/4/2025, 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)).
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
In the Non-Final dated 2/26/2026, the elected species was searched and prior art was identified. Applicant’s response filed 5/19/2026 overcomes the 103 rejection, but the Examiner has reconsidered the art and has provided an additional 103 rejection of the elected species. Thus, this Office Action is considered a second Non-Final. The full scope of the claims has not yet been searched in accordance with Markush search practice. Claims 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 read on the elected species.
Claim Interpretation
Claims 1, 15, and 17 recite the phrase, “therapeutically effective amount” in reference to the amount of castalagin administered to a subject in a method of cancer treatment or a method of enhancing the anti-tumor immune response. The instant specification does not explicitly define this phrase and it is not known to one of ordinary skill in the art. For art purposes, the term “therapeutically effective amount” is currently being interpreted as “effective dose” as disclosed on page 20, line 34 through page 21, lines 1-3 of the instant specification. Administration of castalagin in the Examples of the instant disclosure falls within this range.
Claim 14 recites the phrase, “effective amount” in reference to the amount of immune checkpoint inhibitor administered to the subject. Similar to above, the instant specification does not explicitly define this phrase and for art purposes, it is currently being interpreted as “effective dose” as disclosed on page 20, line 34 through page 21, lines 1-3 of the instant specification.
Claim 15 recites the phrase, “enhancing the anti-tumor immune response in a subject suffering from cancer”. The instant disclosure does not define the term, and it is not generally known to one of ordinary skill in the art. The instant disclosure contains examples of the instant invention; however, it is unclear which example corresponds to the term “enhancing the anti-tumor immune response”. The broadest reasonable interpretation of “enhancing the anti-tumor immune response” includes treating a subject suffering from a cancer. Thus, the term is currently being interpreted as such.
MAINTAINED OBJECTIONS
Objection to Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because Figures 1B, 2B, 3B, 3C, 5B, 7E, and 7F are not able to be interpreted as they are in black and white, but require color to understand. It is unclear what lines correspond to the labels in the drawings. Additionally, Figures 1A, 2A, and 12A are pixelated and illegible, and also require correction. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
NEW REJECTIONS
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 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Kamada (Kamada, Y. et. al. Fitoterapia, 2018, 129, 94-101., cited in the IDS of 9/6/2022), in view of Wang (Wang, Z. et. al. Sci. Rep. 2019, 9, 1853) and Du (Du, W. et. al. JCI Insight. 2018, 3(21), e124184).
Determining the scope and contents of the prior art
The reference Kamada teaches the compounds castalagin and vescalagin, purified from the leaves of Syzygium samarangense, as PARP1 inhibitors (title, abstract). Specifically, Kamada teaches the inhibition of PARP1 by plant extracts (Figure 1), which helps teach claim 6, and specifically teaches that one of the active components of the plant extract was found to be castalagin. Castalagin demonstrated an IC50 against PARP1 of 0.86 uM (Figure 3B). Further, with respect to claims 8-9 and 23-24, the dried plant extracts were reconstituted in DMSO, generating a pharmaceutical composition, and contain cellulose, which help formulate the compositions for intestinal delivery (page 96, section 2.4).
The reference Wang teaches the investigation of the therapeutic potential of the niraparib, a highly selective PARP1/2 inhibitor, and an anti-PD-1 immune checkpoint inhibitor in tumor models (abstract). Specifically, Wang teaches the treatment of KLN-205, a non-small cell lung cancer cell line, with niraparib monotherapy, anti-PD-1 monotherapy, and the combination of niraparib and anti-PD-1 therapy (page 8 and page 9, Figure 5D). The results of the administration of the pharmaceuticals combined indicates an improved benefit over the administration of each pharmaceutical alone. The quantities administered to patients satisfy the limitations of therapeutically effective amounts as per the claim interpretation above.
The reference Du teaches the treatment of cancer with resistance to immune checkpoint blockade by kinase inhibitor sitravatinib (abstract), and specifically teaches that KLN-205 is an aggressive lung cancer model that is resistant to checkpoint blockade (page 5), which includes PD-1 inhibitors.
Ascertaining the differences between the prior art and the claims at issue
The reference Kamada fails to teach the treatment of a cancer resistant to immunotherapy, and thus fails to teach an PD-1 inhibitor, CTLA-4 inhibitor, PD-L1 inhibitor as immune checkpoint inhibitor therapies, an anti-PD-1 blocking antibody, and where the cancer is triple negative breast cancer or non-small cell lung cancer.
The reference Wang fails to teach the compound castalagin in the method of treatment, castalagin in a plant or a fruit extract, a pharmaceutical composition, or a formulation for the delivery of castalagin into the intestines. Further, Wang fails to teach that KLN-205 is a strain that is resistant to immunotherapy.
Finally, Du fails to teach the compound castalagin in the method of treatment, castalagin in a plant or a fruit extract, a pharmaceutical composition, or a formulation for the delivery of castalagin into the intestines, and the treatment of the KLN-205 with a PARP inhibitor.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of treating a subject suffering from a cancer resistant to immunotherapy. An artisan possess the technical knowledge necessary to make adjustments to the methods to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said methods of treating a subject suffering from a cancer resistant to immunotherapy and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
According to KSR prong (B), it would have been prima facie obvious to one having ordinary skill in the art to substitute the teaching of the PARP1 inhibitor niraparib of Wang with PARP1 inhibitor castalagin of Kumada because both compounds are known to have the same target, and the non-small cell lung cancer cell line KLN-205 is known to be resistant to immunotherapy according to Du. Thus, the substitution of niraparib for castalagin would be expected to have similar properties, and a skilled artisan would have been motivated before the effective filing date to make such a substitution to identify additional methods of treating non-small cell lung cancer. A skilled artisan would have reasonably expected success in view of the teachings of Kamada, Wang, and Du.
Close Prior Art Not Cited
Close prior identified during the search is Willemann (Willemann, J. R. et. al. J. Food. Sci. 2020, 85(8), 2358-2367., cited in the IDS of 9/6/2022) which is drawn to the extraction of phenolic compounds from camu-camu seeds (abstract). The optimized lyophilized extract was found to contain castalagin (page 2363, lines 4-7), and had inhibitory activity against cancer cell lines Caco-2, HepG2, and A549 (page 2365, Figure 3). Though castalagin and vescalagin were hypothesized to be responsible for the cytotoxicity and found in a plant or fruit extract, Willemann differs from the instant invention because the cancer is not resistant to immunotherapy, where the immunotherapy is an immune checkpoint inhibitor therapy selected from a programmed cell death-1 inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 inhibitor, or a programmed death-ligand 1 inhibitor. Additionally, no immune checkpoint inhibitor was administered in combination with castalagin to the subject and no anti-tumor immune response in a subject suffering from cancer was enhanced.
Additional close prior art identified during the search is Traber (WO 2014/043708 A1, cited in the IDS of 9/6/2022), which is drawn to methods of enhancing specific immunotherapies in cancer treatments. Specifically, Traber teaches the enhancement of immune and prostate tumor response after treatment of mice with an anti-CTLA-4, an anti-PD-1, or an anti-OX40, followed by administration of galactoarabino-rhamnogalacturonate (page 27, paras [00141]-[00143]) to increase the activation of CD8+ cells (page 28, para [00145]). Furthermore, Traber teaches a similar method applied to breast tumors (page 30, paras [00155]-[00158]), but fails to teach the compound castalagin, the presence of castalagin in a plant or fruit extract, formulation for delivery in the intestines, and the disease treated being non-small cell lung cancer or triple-negative breast cancer.
Conclusion
Claims 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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