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 III (a composition comprising a therapeutically effective amount of Formula (I) or (II)) in the reply filed on 06/29/2026 is acknowledged. Claims 112-131 are directed toward the elected invention.
Priority
Examiner acknowledges that, according to the Filing receipt received 03/12/2025, that the instant application 18/706,551 filed 05/01/2024 is a 371 of PCT/US2022/079177 filed 11/02/2022 which claims benefit of U.S. provisional application 63/274,880 filed 11/02/2021. Claims 112-131 have been awarded the effective filing date of 11/02/2021.
Information Disclosure Statement
The Information Disclosure Statements filed on 07/29/2024 and 08/11/2025 are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of list of references cited from the IDS is included with this Office Action.
Specification
The disclosure is objected to because of the following informalities:
P. 1, par. [0002]: “(ETC.)” should read “(ETC)”;
P. 65, par. [00204]: “cOmplete” should read “complete”.
Appropriate correction is required.
The use of terms such as Glydant® Plus, Phenonip®, Germall® 115, Germaben® II, Neolone®, Kathon®, Euxyl®, etc., (see p. 39 of specification) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Drawings
The drawings are objected to because they are too small and/or of low resolution such that they cannot be interpreted by Examiner. In particular, this is of issue for Figure 1A, 1F, 2A, 2B, 2D, 2E, 3A, 3H, 4A, 4F, 7, 8, 10, 11, and 16. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(a)
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 112-131 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 claim(s) 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 instant claims are drawn a composition comprising a compound of generalized Formula (I) or Formula (II), as below, in combination with an additional pharmaceutical agent such as an anti-obesity agent, a probiotic, an antibiotic, or a statin.
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Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claims indicates that these claims are drawn to a generic genus, i.e., a composition comprising a generic formula for compounds in combination with a generic pharmaceutical agent.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 48 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (48 USPQe2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
The instantly claimed composition encompasses millions of possible combinations, where the very core part of the structure is established in Formula (I) or (II) and the additional pharmaceutical agents vary greatly. Each of these species varies drastically in comparison to the species as defined by the generic composition. Furthermore, applicants have not described any individual compositions comprising a compound of Formula (I) or (II) and an additional pharmaceutical agent. Of the components of the claimed compositions, only compounds of Formula (I) or (II) wherein n or m, respectively, are 8, 9, or 10 are described. Of the thousands of possible agents within the scope of “pharmaceutical agent” or any anti-obesity agent, probiotic, antibiotic, or statin, only antimycin, piericidin, penicillin, and streptomycin are disclosed (see par. [00192] and [00201]). However, it is not evident from the working examples whether these antibiotics (antimycin, piericidin, penicillin, and streptomycin) are ever combined with any compound of Formula (I) or (II) in a composition.
Examiner also notes that in addition to a lack of working examples or species of the claimed compositions, the anticipated benefit and/or effect of the claimed compositions is merely speculative. For example, paragraph [0038] states, “Without wishing to be bound by any particular theory, unwanted depletion of bacteria that produce this rhodoquinone and/or rhodoquinol may have severe implications for mitochondrial function in organs that rely on rhodoquinone as an electron carrier. Thus, the loss of this metabolite after antibiotic treatment may affect patient risk for diseases related to ischemia, and supplementation with rhodoquinone and/or rhodoquinol may protect those subjects.” The working examples, however, are limited to establishing that antibiotic treatment and hypoxia lead to increased fumarate reduction, wherein fumarate functions as an electron input for the ETC when oxygen reduction is inhibited (p. 50-59) while example 6 (p. 67-68) demonstrates that rhodoquinone carries electrons in the ETC and is depleted in the kidneys of mice lacking a microbiome. In no particular example do the applicants demonstrate that rhodoquinone supplementation, either alone or in combination with another pharmaceutical agent, would benefit a subject in a therapeutic capacity.
Generally, the lack of exemplified guidance establishes a reasonable level of doubt that would suggest that the Applicant was not in possession of the various species claimed and thus has not met the written description requirement. Although Applicants describe the compounds of Formula I generally and describe the exemplified embodied substituents, Applicant’s disclosure is silent regarding a number of functionality modifications to the claimed invention thus introducing uncertainty. Applicant does not provide a description that reasonably overcomes the factual understanding that is indicative of the state of the art and that shows that the given possible species, or any related synthon have yet to be established. One of skill in the art would find these factors important in considering the practical application of generating the proposed instantly claimed species. Thus, the claimed compound species of Formula I are neither within Applicant's possession nor reasonably supported by Applicant’s disclosure. While Applicant recites this broad, generic Formula I, Applicant provides no evidence of record that any of the species of this genus are in possession.
In the absence of sufficient guidance, the specification does not provide adequate written description of the claimed genus of compositions, which is generic. One of ordinary skill in the art would not recognize from the disclosure that the Applicant was in possession of the genus. The specification does not clearly allow persons of ordinary skill in the art to recognize that they have invented what is claimed (see Vas-Cath at page 1116).
Claims 112-131 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 pharmaceutically acceptable salts, tautomers, and stereoisomers, does not reasonably provide enablement for solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, or prodrugs. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
1) Amount of guidance provided by applicant. Applicant has demonstrated the biosynthesis of rhodoquinone-9 in mouse kidneys (p. 68 of specifications) However, the instant specification provides no species of Formula (I) or (II) wherein solvates, hydrates, isotopically labeled derivatives, or prodrugs are made. The terms “solvates”, “hydrates”, “derivatives”, “polymorphs”, “co-crystals” and “prodrugs” are incredibly broad.
As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.” The same circumstance appears to be true here. Hence, Applicants must show that solvates, hydrates, or prodrugs of these compounds can be made, or limit the claims accordingly.
2) The nature of the invention and predictability in the art. The invention is directed toward rhodoquinone and rhodoquinol compounds. Regarding predictability in the art, chemistry is generally regarded as unpredictable, particularly the formation of solvates, hydrates, polymorphs, and co-crystals. Moreover, the terms “prodrug” and “derivative” provide no particular guidance as to what structures are encompassed by the instant claims. Additionally see In Re Marzocchi and Horton, 169 USPQ at 367 paragraph 3:
“Most non-chemists would probably be horrified if they were to learn how
many attempted syntheses fail, and how inefficient research chemists are.
The ratio of successful to unsuccessful chemical experiments in a normal
research laboratory is far below unity, and synthetic research chemists, in
the same way as most scientists, spend most of their time working out
what went wrong, and why. Despite the many pitfalls lurking in organic
synthesis, most organic chemistry textbooks and research articles do give
the impression that organic reactions just proceed smoothly and that the
total synthesis of complex natural products, for instance, is maybe a labor-
intensive but otherwise undemanding task. In fact, most syntheses of
structurally complex natural products are the result of several years of
hard work by a team of chemists, with almost every step requiring careful
optimization. The final synthesis usually looks quite different from that
originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who
has experienced for himself the many failures and frustrations which the
development (sometimes even the repetition) of a synthesis usually
implies will be able to appraise such work ......Chemists tend not to publish
negative results, because these are, as opposed to positive results, never
definite (and far too copious)...” Dorwald F. A. Side Reactions in Organic
Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface.
The scope of any compounds, compositions, or pharmaceutically acceptable salts where the variables were not those mentioned above are not adequately enabled or defined. Applicants provide no guidance as how the solvates, hydrates, polymorphs, and co-crystals of the compounds are made.
3) Number of working examples. The compound core depicted as above represents a genus for which Applicant has provided sufficient guidance to make and use; however, this disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the solvates, hydrates, derivatives, polymorphs, co-crystals or prodrugs thereof instantly claimed. Applicant has provided no working examples of any solvates, hydrates, derivatives, polymorphs, co-crystals or prodrugs.
Within the specification, “specific operative embodiments or examples of the invention must be set forth, Examples and description should be of sufficient scope as to justify the scope of the claims, Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
4) Scope of the claims. The scope of the claims is all of the compounds encompassed by Formula (I) and (II) as well as solvates, hydrates, isotopically labeled derivatives, polymorphs, co-crystals and prodrugs thereof.
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The claims are therefore incredibly broad.
5) Level of skill in the art. The artisan using Applicant’s invention would be a chemist with a Ph.D. degree and having several years of bench experience.
6) Undue experimentation. 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)."
The conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 112-113, 115, and 117 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Plat et al. (WO 2020/130813 A1; IDS filed 07/29/2024) as evidenced by PubChem (National Library of Medicine; created 2006).
Plat et al. discloses a composition extracted from Rhodospirillum rubrum cells comprising an effective amount of rhodoquinone-10, carotenoids, ubiquinones, and bacteriopheophytins (p. 67, lines 19-23) which resulted in reduction in LDL-cholesterol concentration in mice (p. 67, lines 24-31). As evidenced by PubChem, rhodoquinone-10 has the following structure (p. 2-3).
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The compound is a species of Formula (I) wherein n is 9.
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.
Claim(s) 114, 116, and 118-131 is/are rejected under 35 U.S.C. 103 as being unpatentable over Plat et al. (WO 2020/130813 A1; IDS filed 07/29/2024) as evidenced by PubChem (National Library of Medicine; created 2006), applied to claims 112-113, 115, and 117 above, and further in view of Grammel et al. (Journal of Bacteriology; 2008), Le Roy et al. (BMC Biology; 2019), and Heal et al. (British Journal of Clinical Pharmacology; 2009).
Plat et al. discloses as above. Plat et al. does not disclose a composition wherein n (or m) is 8 or 10 in the compound of Formula (I) (or Formula (II)), that the additional pharmaceutical agent is an anti-obesity agent, a statin, an antibiotic, or a probiotic. Plat et al. does not disclose a composition comprising a compound of Formula (II). These limitations are obvious over Plat et al. in view of Grammel et al., Le Roy et al., and Heal et al.
Plat et al. additionally discloses an embodiment wherein the composition is administered with another pharmaceutical ingredient such as a statin in order to improve the cholesterol-lowering effect (p. 33, line 36 – p. 34, line 10; p. 36, lines 4-11).
Grammel et al. discloses rhodoquinol-10, the reduced form of rhodoquinone-10 (p. 4913, col. 2, par. 4). Grammel et al. discloses that rhodoquinol-10 is a known quinone present in Rhodospirillum rubrum (R. rubrum) (p. 4916; col. 1; par. 2).
Le Roy et al. discloses that microbiota depletion in mice, caused by treatment with antibiotics, raises plasma cholesterol levels and enhances cholesterol synthesis in the liver (p. 4 whole page; p. 7, col. 1, par. 1) and that intestinal microbiota helps in regulating cholesterol absorption and synthesis (p. 9-10). Le Roy et al. additionally suggests the use of probiotics to treat cardiovascular diseases, wherein elevated plasma cholesterol is a risk factor (p. 1, col. 2; p. 15, col. 2).
Heal et al. discloses that elevated low-density lipoprotein (LDL)-cholesterol is a metabolic consequence of obesity (p. 861-862, bridging paragraph). Heal et al. discloses that while some anti-obesity drugs show improvements in plasma lipid profiles in obese patients with hypercholesterolemia, few have been shown to lower LDL-cholesterol and anti-obesity drugs themselves have not been approved for the treatment of dyslipidemia (p. 869, whole page).
It would have been prima facie obvious for one of ordinary skill in the art to formulate the composition of Plat et al. with rhodoquinol-10. One would have been motivated to do so, with reasonable expectation of success, as rhodoquinol-10 is the reduced form of rhodoquinone-10, both of which are known quinones found in R. rubrum cells. One of ordinary skill in the art would therefore reasonably expect that some amount of the rhodoquinone-10 in the composition of Plat et al. would be present in the reduced form. Moreover, regarding the limitation wherein n or m is 8 or 10, compounds that differ by the number of monomers in a polymer are considered homologs. In re Hoke 195 USPQ 148. Since a compound of Formula (I) or (II) wherein n or m is 8 or 10 is considered a homolog of a compound of Formula (I) or (II) wherein n is 9, these compounds are considered equivalent. The MPEP 2144.09 states “Compounds which are… homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
It would be prima facie obvious for one of ordinary skill in the art to combine the composition of Plat et al. with a statin, antibiotic, probiotic, or anti-obesity medication. One would have been motivated to do so, with reasonable expectation of success, in order to enhance the cholesterol-lowering effect of the composition of Plat et al., to maintain cholesterol levels upon administration of an antibiotic, or to treat comorbidities associated with obesity that are not sufficiently treated by anti-obesity medications.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MADELINE E BRAUN whose telephone number is (703)756-4533. The examiner can normally be reached M-F 8:30am-5:00pm ET.
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/MADELINE E BRAUN/Examiner, Art Unit 1624 07/21/2026
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