DETAILED ACTION
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 .
Status of the Claims and Response to Restriction Requirement
Claims 2-3 and 7-13 are pending as of the response filed 02/03/2026. Claims 1 and 4-6 are cancelled in the response dated 02/03/2026. Applicant’s election of group I claims and a species of compound, ACK900 is acknowledged. Claims 2-3 and 7-8 encompass the elected species. Applicant’s remarks regarding the prior art cited in the restriction requirement, WO 2020/015816 A2, that it no longer teaches the special technical feature shared by the inventions of group I and II, is acknowledged and was found to be persuasive.
The elected species was examined and found to be free of prior art. Therefore, the examiner has extended the search of the Markush-type claim to include all species encompassed by formula (II), as in claim 2. The compounds of formula (II), as in claim 2 have been found to be free of prior art.
In consideration of Applicant’s remarks and since the compounds of formula (II) are free of prior art (claims 2-3 are allowable), pursuant to the procedures set forth in MPEP § 821.04(b), claims 9-13, directed to the process of making or using the allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 12/09/2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 2-3 and 7-13 are examined herein.
In view of the pending claims, the following objections and rejections are made.
Priority
This application is a 371 of PCT/US2022/020074 filed 03/11/2022, which claims priority to PRO 63/161,580 filed 03/16/2021.
The subject matter of claims 2-3 and 7-13 are supported by PRO 63/161,580 filed 03/16/2021 and accordingly, have an effective filing date of 03/16/2021.
Drawings Objected To
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112 - Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for selectively inhibiting α-hGMII comprising administering the compounds or pharmaceutical compositions of formula (II), does not reasonably provide enablement for a method of treating all types of cancers, because “treating” is defined to encompass prevention. 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. 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 re Wands, 8 USPQe2d 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/The nature of the invention
The claim recites a method of treating a subject having a cancer comprising administering to the subject an effective amount of the pharmaceutical composition comprising the compound of formula (II). The instant specification defines “treatment” with reference to the treatment of cancer as encompassing an agent (i.e., the present
compound) that does not necessarily cure, but delays hinders or prevents the onset of the disease or condition (Para. [0066] of the instant specification). Therefore, the scope of the method claims is extensive, as they encompass not only ameliorating the symptoms but also preventing each and every type of cancer by the administration of said compounds.
The state of the prior art/The level of predictability in the art
Pinho et al. (Glycosylation in cancer: mechanisms and clinical implications, 20 August 2015, hereinafter Pinho); Bianchi et al. (Not all cancers are created equal: Tissue specificity in cancer genes and pathways, 21 February 2020, hereinafter Bianchi); Serrano et al. (Therapeutic cancer prevention: achievements and ongoing challenges – a focus on breast and colorectal cancer, 21 February 2019, hereinafter Serrano).
Pinho teaches that despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer (Abstract). Pinho teaches that alterations in glycosylation
regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention (Abstract). Pinho teaches tumor cells display a wide range of glycosylation alterations compared with healthy cells. Pinho teaches aberrant glycan modifications are protein specific, site-specific (different sites on a given protein can be differentially glycosylated) and cell-specific. Pinho teaches specificities of glycosylation depend on various
intrinsic factors of the glycosylation process within a given cell or tissue type (Pg. 541, second column, last paragraph). Pinho teaches some of the most common clinically utilized serological biomarkers for cancer diagnosis and monitoring of malignant progression, as well as prognostic biomarkers of disease recurrence, are glycoproteins (Pg. 550, second column, last paragraph), the most prominent being PSA for prostate cancer, CA125 for ovarian cancer, CA15-3 for breast cancer, etc. (Pg. 551, first column, continued paragraph). Pinho teaches that although these serological biomarkers have been shown to have an aberrant glycosylation in cancer, they have limited application owing to their relative low specificity, precluding their use for screening strategies and diagnostic potential (Pg. 551, first column, continued paragraph). Pinho teaches that serum fucosylated haptoglobin is a specific biomarker for pancreatic cancer compared to other cancers or healthy controls. Pinho teaches combining glycan analysis with protein markers enhances diagnostic and prognostic performance (Pg. 551, second column, continued paragraph). Pinho concludes by highlighting the need to integrate multiple, high-dimensional biological data layers—specifically adding glycomics and glycoproteomics to the established fields of genomics, transcriptomics, proteomics, and metabolomics to effectively diagnose and treat cancer owing to its the complexity (Pg. 552, first column, last paragraph – second column, continued paragraph).
Bianchi teaches that the vast majority of cancer driver genes are mutated in a tissue-dependent manner, that is, are altered in some cancers but not others (Abstract). Bianchi teaches that both cell-intrinsic and cell-extrinsic factors play a role in the development of cancers by affecting cell autonomous pathways (Abstract; Figure 2). Bianchi highlights that while tumors often inherit the immune microenvironment of their original tissue (for example, colon or stomach cancers and brain or liver tumors), there are some exceptions (Pg. 140, first column, first full paragraph). Bianchi teaches melanoma, head and neck, and kidney cancers, show significantly higher IFN-γ, T and NK cell infiltration compared to their adjacent healthy tissue (Pg. 140, first column, first full paragraph). Bianchi teaches pancreatic adenocarcinoma often displays a myeloid-inflamed stroma that acts as a barrier, resulting in a weak response to immunotherapy (Pg. 140, first column, first full paragraph). Bianchi concludes the crosstalk between cell type-specific rewiring of signaling pathways and tissue type-specific microenvironment shapes the tumor type-specific mutational frequency of cancer driver genes, as well as response to therapy (Pg. 140, second column, first full paragraph).
Serrano teaches the lack of an objective marker to target with preventive cancer therapies makes it more difficult for physicians to advise, and for candidates to undergo, treatment without a measurable outcome, particularly as they may not themselves experience a benefit but could suffer side effects (Pg. 587, first column, first full paragraph). Serrano teaches effects on cancer occurrence, as the definite endpoint, can take decades to evaluate (Pg. 580, second column, continued paragraph).
Therefore, the state of the prior art indicates unpredictability and complexity with respect to glycosylation pathways and that cancer is not a single disease entity with a simple, linear cause, but rather a complex, heterogeneous, and dynamic system that requires a multi-layered, holistic understanding to effectively diagnose and treat. The state of the prior art indicates that cancer drivers are not universal but highly tissue-dependent, shaped by the cell-of-origin's specific signaling, environment, and epigenetic context. It is also clear that cancer prevention is not well-established or predictable in consideration of the art.
Additionally, it is noted that the state of the art with regard to pharmacology is unpredictable. The field of pharmacology involves screening compounds both in vitro and in vivo to determine lead compounds that exhibit the desired pharmacological activity. According to MPEP 2164.03, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).”, with physiological activity being considered to be an unpredictable factor.
Therefore, in consideration of the high level of unpredictability in the field of cancer treatment/prevention, it is unclear how the claimed method would achieve the intended result of treating all types of cancers, including prevention, comprising administering the compounds of the instant invention knowing that effects on cancer occurrence can take decades to evaluate.
The level of one of ordinary skill in the art
The relative level of skill in the art is high, such as, a synthetic organic chemist, healthcare professionals such as, an oncologist or molecular biologist with advanced educational degrees (e.g., M.D. and/or Ph.D.). Additionally there is significant unpredictability in the art regarding the development of therapies, due to the heterogenous nature of cancers.
The amount of direction provided by the inventor/The existence of working examples
Applicants have provided in vitro assays that indicate the example compounds exhibit the desired selectivity for specific inhibition of α-hGMII in comparison to α-hLM (Para. [00161], Table 1 of the instant specification). Applicant’s assays indicate the antiproliferative activity of these compounds towards a handful of cancer cell lines (liver cancer, pancreatic cancer, lung cancer and triple-negative breast cancer). Applicants have in vivo data showing considerable reduction in tumor volume when mice were administered the compounds of the invention versus vehicle, for liver cancer (FIG. 4B). However, the disclosure does not indicate how the disclosed data correlates with the treatment of all types of cancers, including prevention. There is lack of direction or guidance regarding treatment of all types of cancers using the compounds of the invention. The given data support treatment of cancers responsive to inhibition of α-hGMII activity.
The quantity of experimentation needed
Considering the state of the art as discussed in the references above, high degree of unpredictability in the field, and lack of sufficient guidance in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 7-8, the claim depends from cancelled claim 1 and therefore, lacks sufficient antecedent basis.
For the purpose of applying prior art, claims 7-8 have been interpreted as depending from claim 2 to provide sufficient antecedent basis.
Claims 9-13 either directly or indirectly depend from claim 8 and are similarly rejected.
Allowable Subject Matter
The compounds of formula (II) as in claim 2 have been found to be free of prior art.
The following is a statement of reasons for the indication of allowable subject matter:
The instant application relates to a compound of general formula (II), with variables as defined in instant claim 2, a pharmaceutical composition and a method of treatment thereof.
The closest prior art of record is Wilson et al. (WO 2010/015816 A2, 11 February 2010, hereinafter Wilson) and Chen et al. (Divergent Synthesis of Bicyclic Iminosugars: Preparation of (-) Swainsonine-based Alkaloids and Their Inhibition Study towards α-human Mannosidases, 03 November 2019, hereinafter Chen).
Wilson teaches an exemplary compound, compound 857, (1R,2R,3R,7S,7aR)-3-((benzylaminomethyl)hexahydro-1H-pyrrolizine-1,2,7- triol (Pg. 162, sixth compound) having the following structure.
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Compound 857 of Wilson differs from the instantly claimed compounds in the hexahydro-1H-pyrrolizine versus octahydroindolizine bicyclic ring and the absence of the required
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grouping in the molecule.
Chen teaches swainsonine analogues for inhibition study against
both α-hLM and α-hGMII, with the C8 hydroxyl group in proper orientation playing a crucial role for inhibitory activities (Abstract). Chen teaches the following polyhydroxylated pyrrolizidine and indolizidine-based molecules (Figure 1).
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However, there is no teaching or suggestion in the prior art to arrive at the compounds of the instant invention. Therefore, the instant compounds are novel and non-obvious over the closest prior art of record.
Conclusion
Claims 7-13 are rejected.
Claims 2-3 are allowed.
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/PADMAJA S RAO/Examiner, Art Unit 1627