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, claims 1-3, 5-6, 8-9, 11-12, 14-18, 20-21, 23-24, and 26-27 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. The reference struck through in the IDS submitted on 9/6/2022 was not considered because it did not contain an English translation of the abstract.
Objection to Abstract
The abstract is objected to for a minor grammatical informality: The plant name Myrciaria dubia should be italicized, and read, “Myrciaria dubia”. Appropriate correction is required.
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.
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.
The elected species was searched and prior art was identified. See the 103 rejection below. 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.
Claim Objections
Claims 3 and 18 are objected to as they recite “Programmed cell death-1” and “Programmed death-ligand 1”, but should read, “programmed cell death-1” and “programmed death-ligand 1”, as they are not proper nouns. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-6, 9, 11-12, 14-18, 20-21, 24, and 26-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, the claims of the instant application embrace castalagin or an analog thereof. Particularly, the term “analog” recited in claims 1, 6, 9, 15, 21, and 24 invokes the 35 U.S.C. 112(a) rejection, and claims 2-3, 5, 11-12, 14, 16-18, 20, and 26-27 depend from the above claims. Even a cursory calculation of the number of compounds embraced in the instant claims would result in thousands of compounds.
Level of skill and knowledge in the art
The level of skill and knowledge in the art is high.
Partial Structure
Castalagin and analogs thereof have been disclosed and example compound species that would be within the general formula have been disclosed on page 17, lines 3-14 of the specification, and include compounds such as lyxose, xylose, casuarinin, and castalin. However, as to the claimed analogs of castalagin, no specific examples are given that would demonstrate possession or put the public in possession of all the claimed analogs of castalagin. It is generally accepted that analogs may vary by chemical formulae and may also differ in properties and the arrangement of atoms in the molecule.
Physical and/or chemical properties/functional characteristics
Castalagin and analogs thereof are compounds which are allegedly useful in treatment of cancer. Although the art recognizes generally accepted definitions, the terms is not explicitly defined by the specification in such a way as to demonstrate that the inventor had possession of the analogs of castalagin.
A review of the art identifies the reference Messaoudene (Messaoudene, M. et. al. Cancer Discov. 2022, 12(4), 1070-1087.), which is drawn to the administration of castalagin to treat cancer (abstract). Specifically, Messaoudene discloses that the action of castalagin is specific because closely related metabolites, such as castalin, and it’s diastereomer, vescalagin, did not exhibit antitumor activity in vivo (Figure 7A and discussion section, third paragraph). However, castalin is listed in the instant specification as an analog on page 17, line 4. Thus, Applicants’ own work argues that analogs or closely related metabolites of castalagin do not all contain antitumor activity, and thus a structure/function relationship is not established. Consequently, a common utility cannot be expected with the analogs of castalagin recited in the instant claims and one of ordinary skill in the art would not be able to predict which analogs will be active or inactive absent evidence.
Since Applicant has not set forth all analogs in the specification which Applicant considers active, it is not clear what compounds fall under analogs of castalagin. Applicant has not described which analogs have the ability to treat cancer, and which do not. Stated differently, there is no structure/function correlation and no representative number of specific examples of analogs that demonstrate which compounds retain activity. Further, one of ordinary skill in the art would not be able to predict the biological activity of the claimed analogs of castalagin.
Predictability of the art
Medicinal chemistry is an experimental science with a low predictability level. Small changes in the structure of a compound can lead to large differences in their pharmacological activity. Regarding analogs, predicting if a certain claimed compound retains the activity and function of the original drug is filled with experimental uncertainty because analogs contain variation by chemical and physical properties of the molecules.
Method of making the claimed invention
Although the specification refers to the prior art for isolation of castalagin, no method for isolating or synthesizing all of the analogs encompassed by the instant claims has been disclosed. Methods of synthesizing and isolating compounds are, in general, known to a person of ordinary skill; however, methods of isolating or making the myriad of analogs encompassed by the instant claims is beyond the skill of the artisan, particularly when certain elements, are merely described partially.
As such, the instant specification and instant claims do not provide sufficient description such that one could anticipate what additional elements may be present in the analogs of castalagin because the examples illustrated in the specification are only limited to a small group.
Substantial and undue experimentation would be needed to practice Applicant’s invention because the specification lacks sufficient detail to show how to use the analogs of the instant invention. Further, there is no guarantee that all of the analogs embraced by the scope of the claims would be use in treatment of cancer.
Even with the undue burden of experimentation, there is no guarantee that one would obtain the product of a desired analog of castalagin. Although some functional characteristics are disclosed or would be known to a person of ordinary skill in the art, in the absence of a disclosed structure, there can be no correlation between the function and structure of the claimed analogs in the instant application.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claim(s) are broad and generic with respect to all possible compounds encompassed by the claims: the possible structural variations are limitless to any analogs of castalagin. In the instant case, however, the specification does not disclose a sufficient variety of species to reflect this variance in the genus. Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims such as analogs of castalagin
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Dependent claims 2-3, 5, 11-12, 14, 16-18, 20, and 26-27 do not resolve the 112(a) written description rejections raised in claims 1, 6, 9, 15, 21, and 24, since those claims do not further limit or provide further structure of the analogs of castalagin. Accordingly, these claims are also rejected. This rejection would be overcome by amending the claims to remove the terms, “analog”.
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), and further in view of Clinical Trial NCT03334617 (https://clinicaltrials.gov/study/NCT03334617?tab=history&a=22#version-content-panel, V22 2020-01-31, accessed 2/21/2026).
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).
Clinical Trial NCT03334617 teaches a method of treatment of non-small cell lung cancer patients whose cancer has progressed while on anti-PD-1/PD-L1 containing therapy, indicating resistance to PD-1 and PD-L1 (page 11, detailed description). Patients were given 500 mg Q4W ±2 days dervalumab and 300 mg BD olaparib, a PARP1 inhibitor, to treat the cancer (page 13, Arms and Interventions). The quantities administered to patients satisfy the limitations of therapeutically effective amounts as per the claim interpretation above.
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.
Clinical Trial NCT03334617 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.
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 PARP1 inhibitor olaparib of clinical trial NCT03334617 with PARP1 inhibitor castalagin because both compounds are known to have the same target. Thus, the substitution of olaparib 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 and Clinical Trial NCT03334617.
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