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 .
Election/Restrictions
Applicant’s election without traverse of Group I, corresponding to claims 15, in the reply filed on November 20, 2025, is acknowledged. Further, Applicant elects spermidine, guanosine 5’-monophosphate, inosine 5’-monophosphate, and arthritis as the species.
Status of the Claims
Claims 1-27 are pending. Claims 16-27 are withdrawn. Claims 1-15 are examined.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
Claim 14 is 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. Claim 14 refers to the cell is a cell in a subject and claim 14 depends from claim 9. Claim 9 however refers to two cells. One cell is a cell to contact and the second cell is a an apoptotic cell from which a metabolite is derived. Claim 14 could mean that a modulating of gene expression requires contacting a cell in a subject. Alternatively, it could mean that the metabolite is derived from an apoptotic cell in a subject.
Claim Rejections - 35 USC § 112-Paragraph
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 1-15 are 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 treating arthritis and colitis, e.g., does not reasonably provide enablement for the treatment and prevention (see definition of treatment in the instant Specification) of a subject having any inflammatory condition with any combination of metabolites derived from an apoptotic cell. Similarly, is does not provide enablement for modulating gene expression with any combination of metabolites derived from an apoptotic cell. 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.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include 1) the nature of the invention; 2) the breadth of the claims; 3) the unpredictability of the art; 4) the amount of direction or guidance presented; 5) the presence or absence of working examples; 6) the quantity of experimentation necessary; 7) the state of the prior art; and, 8) the relative skill of those skilled in the art.
The relevant factors are addressed below on the basis of comparison of the disclosure, the claims and the state of the prior art in the assessment of undue experimentation.
The Breadth of the Claims
The presently claimed invention is directed to a method of treating and preventing any inflammatory condition with any combination of apoptotic cell derived metabolites. The claims embrace prophylaxis in the definition of treatment, as a patient “at risk of developing” or “suspected of having” does not actually possess an inflammatory condition prior to the administration of a metabolite combination. None of the working examples support prevention, as explained in more detail below.
The Nature of the Invention
The claimed invention is directed to the treatment and prevention of all inflammatory conditions with any metabolite combination derived from apoptotic cells.
Level of Ordinary Skill in the Art:
The level of skill in the art is high, requiring an advanced degree in biochemistry and medicine.
The State of the Prior Art and Unpredictability in the Art
Zeng et al., “A Commentary on Metabolites released from apoptotic cells act as tissue messengers,” (2020) Frontiers in Immunology August 2020, Vol 11, Article 1878; explains: “However, with the rapid discovery of new mechanisms of apoptosis, the roles played by intracellular changes in apoptotic cells and their metabolites are not entirely clear.”
Therefore, these findings indicated that apoptosis cells were able to produce anti-inflammatory mediators and inhibit inflammation. However, a very recent study demonstrated that cytotoxic CD8+ T cells mediated ICD through the caspase-3 dependent pathway on cancer cells to generate pro-inflammatory factors which is involved in elimination of tumor cells (8). Thus, these apparent contradictory findings suggest that anti-inflammatory properties of apoptosis might be context dependent, and designed strategies to use apoptosis as anti-inflammatory therapy would require a major understanding of the mechanisms involved and likely specific analyses in every disease.
Jiang et al., “The association between dietary creatine intake and cancer in U.S. adults: insights from NHANES 2007–2018,” Frontiers in Nutrition, July 2024, teaches: creatine might suppress tumor growth by enhancing CD8+T cell activity. However, when it is converted to phosphocreatine, it may supply ATP to cancer cells, potentially aiding metastasis and invasion. See p2, 4th par.
In other words, it is not likely that all inflammatory conditions can be treated with the claimed metabolites as their intracellular roles are not entirely clear.
As established supra, the treatment and prevention of any inflammatory condition in a subject merely at risk of having an inflammatory condition by following the claimed guidelines was unpredictable at the time of the invention. It is not clear that the claimed metabolite combination of can treat and prevent all inflammatory conditions. While the elect combination was shown to have anti-inflammatory efficacy against models of arthritis and lung transplant rejection, it is not establish that combinations lacking spermidine, IMP, and GMP would treat, let alone prevent, all inflammatory conditions.
Amount of direction provided by the inventor and existence of working examples:
The Specification indicates that the number of metabolites compared to the identified five ‘conserved’ metabolites is substantial. AMP, GMP, creatine, spermidine, and glycerol 3-phosphate, as well as ATP were identified as shared through screenings. See Fig. 1B and 7A. The Specification evaluated/observed only two combinations of metabolites as having anti-inflammatory activity and noted that the in vivo dose of glycerol-3-phosphate was difficult to determine. See Example 6. The Specification describes testing an arthritis model and a lung transplant rejection model. Moreover, the only combination of metabolites tested was: Group I utilizing: spermidine, fructose-1,6-bisphosphate, dihydroxyacetone phosphate, UDP-glucose, guanosine monophosphate, and inosine monophosphate; and Group II utilizing: spermidine, guanosine monophosphate, and inosine monophosphate. Thus, none of the groups include less than three metabolites and each group tested included at least the elected species combination of spermidine, IMP, and GMP.
As discussed above, the working examples in the specification provide a specific combination of metabolites for treating two distinct inflammatory models. Arthritis and lung transplant rejection were the sole models tested with metabolite combinations requiring: spermidine, IMP, and GMP. Thus, the working examples do not demonstrate that a generic subject with, or at risk of, any inflammatory condition can be treated with any combination of metabolites derived from an apoptotic cell of any type.
In light of such, it is clear that one of ordinary skill in the art would be faced with the impermissible burden of undue experimentation in order to execute the entire scope of the subject matter presently claimed, including analyzing different combinations of metabolites as well as subjects having or at risk of any inflammatory condition. The basis for the present rejection is not simply that experimentation would be required, since it is clear from the state of the pharmaceutical and chemical arts that experimentation in this particular art is not at all uncommon, but that the level of experimentation required in order to practice this aspect of the invention in the absence of any enabling direction by Applicant would be undue. Please reference In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976), which states, "The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue."
Given the high degree of unpredictability noted and recognized in the art above coupled with the lack of working examples of demonstrating the capacity of the claimed combination of metabolites to treat and prevent all inflammatory conditions, the encompassed scope of the pending claims is determined to be not enabled. In the absence of any direction or guidance presented by Applicant as to how such a therapeutic objective could be achieved without necessitating an undue level of experimentation, the present disclosure is viewed as lacking an enabling disclosure of the entire scope of the presently claimed subject matter.
To obviate this rejection, the examiner proposes the following amendments to the claims:
Limit the claims to treatment not prevention of a subject in need thereof;
Claim a specific condition or conditions that are established as treatable with a combination; and
Incorporate a specific metabolite combination into the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Salzman et al., (US2003/0040502), in view of Perlmutter et al., (US02013/0338098), in view of Gurny et al., (US2013/0017197).
The examiner notes that the phrase “derived from an apoptotic cell” is defined on page 26 of the instant Specification to mean, in part, that the compounds are associated with or found in an apoptotic cell. Thus, this is interpreted as a description of where such compounds exist. This does not presently require the compounds to come from (i.e., be taken from) a particular source.
Salzman teaches compositions for treating inflammatory conditions of the joints, including arthritis, such as rheumatoid and osteoarthritis. See par. 238. A preferred compound includes IMP. See par. 234. Example 6 tests IMP against inflammatory bowel disease. See par. 288. Paragraph 230 explains that the compounds including inosine 5’-monophosphate can be used to treat many inflammatory disorders and diseases. See par.’s 230, 234, and 238. Also see prior art claims 1-3, 6, and 9, e.g. A carrier is contemplated for use with the composition. See par. 33 and 34, e.g. Formula I is shown in paragraph 62, with a PO32- in the position of R1. Finally, Salzman cites another reference in teaching that IMP is shown to have an additive effect in resolving inflammatory response when combined with aspirin. See par. 14. Compositions can be administered through many routes of administration including oral, IM, IV, topically, and others. See par. 260. The compounds can be administered with additional agents useful as a combination, including an immunosuppressant, NSAID, and other additional APIs. See par. 246. The inosine compounds can be administered at a dose of about 0.01 g to 20 g. See par. 248.
Perlmutter teaches compositions for treating arthritis and rheumatism. See par. 24. Table 2 is directed to evaluating arthritis pain in a subject. The method comprises administering an aliphatic polyamine, including spermidine among a limited list. See prior art claims 42 and 45. Moreover, spermidine can treat arthritis and rheumatism. See prior art claim 54. A diluent or carrier is contemplated. See par. 29 and 32, e.g. Perlmutter also teaches topical administration. See prior art claim 42.
Finally, Gurny teaches a method for treating and ameliorating conditions including rheumatoid arthritis by administering a compound of formula (I), such as guanosine 5’-monophosphate or a salt or tautomer thereof. See prior art claims 32, 42 and 44. Arthritis is preferred among a limited list of conditions. See par.’s 30, 34, and 35. Incorporation of a liquid carrier is contemplated. See Abstract. Routes of administration include topical, parenteral, IV, IP, IM, and others. See par. 98.
With regard to claims 7 and 9, when an effective amount of the claimed agents is used to mitigate arthritis as taught by the cited prior art, absent evidence to the contrary, such active step of administration would modulate gene expression. One reason for this is that the claimed agents are known result effective variables taught to treat a subject with arthritis, e.g. See M.P.E.P. § 2144.05. Similarly, when the elected combination is administered to a subject, absent evidence to the contrary, it would induce an anti-inflammatory or other response that is secondary to the active step of administration.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed methods in view of the cited prior art. One would be motivated to do so because spermidine, GMP, and IMP are each taught for independent use in treating conditions such as arthritis and rheumatoid arthritis. "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." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In this case, because spermidine, GMP, and IMP are each known to treat arthritis, e.g., it would be obvious to administer them to a subject with arthritis and such administration could be in a single or multiple dosage forms administered simultaneously, sequentially, or even in a single form. One would do so because they are obvious to administer and there is no reason that they could not be administered at an optimized time through routine experimentation. As such, there is a reasonable and predictable expectation of success in arriving at the claimed methods in view of Salzman, Perlmutter and Gurny.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628