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
Claims 1-7, 14-25, and 33-40 are pending. Acknowledgment is made of Applicant’s amendments filed April 14th, 2026 and cancelation of claims 8-13 and addition of claims 35-40.
Election/Restrictions
Applicant’s election without traverse of Group V, claim 34,in the reply filed on April 14 is acknowledged.
Applicant’s election without traverse of dimethyl 2,2'-dithiodi-benzoate (depicted below) in the reply filed on April 14 is acknowledged.
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Claims 1-7, 14-25, and 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 14th, 2026.
Claims 34-40 are presently under examination as they relate to the elected invention Group V and species of dimethyl 2,2'-dithiodi-benzoate.
Priority
This application claims priority to US Provisional App. No. 63/216,429, filed June 29th, 2021, and is a 371 of PCT/US2022/035558, filed June 29th, 2022.
Drawings
The drawings are objected to because of the following reasons:
Fig. 1A: The legend labels are pixelated and hard to read.
Fig. 1B: The vertical and horizontal axis labels, as well as the vertical axis scale, are blurry and hard to read.
Fig. 1B: The horizontal axis label, both vertical axis labels, and the vertical axis scale are all blurry and hard to read. In addition, the label on the figure itself above the peak labeled α is blurry and hard to read.
Fig. 2B: The chemical structures are blurry and pixelated.
Figs. 3A-3C: The chemical structures are pixelated, and the vertical and horizontal axis labels and scales are all illegible.
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.
Specification
The disclosure is objected to for the following reasons:
The chemical structures in Table 1, pp. 31-41, are blurry and faded.
Appropriate correction is required.
Claim Objections
Claim 40 is objected to because the structures are faded and hard to read.
Appropriate correction is required.
Claim Rejections – Improper Markush
Claims 34-40 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of compounds represented by formula (I) recited in claim 34 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Markush grouping is directed to compounds of formula (I) or pharmaceutically acceptable salts thereof:
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The variables of rings A1 and A2 and substituents R1a and R1b encompass a myriad of substituents forming compounds so diverse that they will confer the above structure completely different structural and biological properties. For example, A1 and A2 can be six-membered aromatic or heteroaromatic, substituted with any number of heteroatoms. Moreover, the variables m and n can each be from 0-4, further broadening the potential claimed core structures.
With the myriad of compounds that arise from the various definitions and combinations of the variables present in this formula, the result is a group of compounds that include a variety of substitution patterns and core structures resulting in compounds with no single structural similarity that are not obvious variants of each other. To this end, a comparison of three compounds of formula (I) presented in claim 40 demonstrates a lack of significant structural similarity and shows compounds of the formula recited in instant Claim 34 are not obvious variants of each other:
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Outside these examples explicitly claimed, the Markush structure embodies further variability and lack of structural similarity when A1 and A2 are taken to be heteroaromatic and when m and n are taken to be numbers other than 0.
As these compounds demonstrate, the compounds according to the formula (I) include compounds with no common core structure that are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
112(a) – Scope of Enablement
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.
Scope of Enablement – Treatment
Claims 34-40 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 a method of , does not reasonably provide enablement for treating or preventing. 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.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention is drawn to a method of treating, preventing, reducing the occurrence of, or reducing, ameliorating, or alleviating the symptoms associated with presbyopia, cataract, or other conditions or disorders associated with the eye comprising administering a compound of formula (I).
The relative skill of those in the art is high, generally that of a M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
With regard to the unpredictability of eye disease, Timsina et al. (Membranes 2021, 11, 447) teach that the causes of cataract include aging, eye injury, genetics, radiation, high myopia, smoking, medications, significant alcohol consumption, obesity, hypertension, and diabetes (p. 2, para. 2). Given the broad range of potential causes for cataract and unpredictable nature of how these causes and factors may interact, it is impossible to fully prevent all of these causes by simply administering a compound. Furthermore, the category of “eye diseases” include diseases with complex and potentially opposing pathologies and causes, such as myopia (near-sightedness) and hyperopia (far-sightedness).
The breadth of the claims
Claims 34-40 are very broad in claiming the treatment of all types of eye disorders and symptoms associated with eye disorders. Claims 34-40 also recite the prevention of such diseases, further broadening the scope.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides examples of administering compounds of formula (I) to protect ex vivo porcine lenses UV-induced opacification (Table 1, pp. 31-41). However, this mechanism is insufficient to enable for the full scope of diseases encompassed by eye diseases and disorders.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that the compounds of claim 34 and formula (I) could be used to treat, let alone prevent, all types of eye diseases and disorders.
Determining if a particular compound will treat any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicant.
Accordingly, the inventions of claims 34-40 do not comply with the scope of enablement requirement of 35 U.S.C 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Scope of Enablement – Compounds
Claims 34-40 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 compounds of formula (I) wherein A1 and A2 are phenyl substituted with R1a and R1b- as claimed, and wherein m and n are both 0, does not reasonably provide enablement for the full scope of variables of A1, A2, m, and n in the instant claims. 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 and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to compounds of Formula (I) given below, or a pharmaceutically acceptable salt thereof.
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Breadth of the invention:
The scope of the claimed invention is very broad as the variables A1, A2, R1a, Rab, m, and n allow for a multitude of combinations and thus compounds defined by the claims. A1 and A-2 can be six-membered aromatic or heteroaromatic, allowing for numerous substitution sites and heteroatoms within these rings.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Tautermann (Quantum Mechanics in Drug Discovery, Humana Press, 2020, Chapter 1, pp. 1-17), cited for evidentiary purposes, teaches drug discovery is a very challenging, cost-intensive, and in terms of investment risky endeavor; on average, it takes 10–15 years and an investment of more than 2.5 billion dollars to get a new drug to the Market; especially the clinical phases cause extremely high costs and late-stage failures, especially in phase II studies, are quite common (page 1, 1st paragraph). Tautermann teaches the largest attrition in clinical phases is observed in phase II studies; the main goal is the assessment of the efficacy of the compound yielding a clinical proof of concept; a recent analysis from four major pharma companies revealed that the cause for attrition in phase II is mainly caused by lack of efficacy followed by safety issues; efficacy for a certain indication is usually preclinically tested in animal models; however, the translatability from animal models to the human situation is not always given; there are several reasons for this; often the disease condition cannot adequately be induced in animals (page 3, last paragraph). Tautermann teaches small molecules have several advantages, such as being cell and brain permeable, the lower cost of goods in their production, and oral administration; however, they are not always the easiest path forward for challenging targets; especially in the case of difficult or so far undruggable targets, new design strategies are required to be successful (page 5, last paragraph). Thus, Tautermann further establishes that the state of the art of drug design is highly unpredictable.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where m and n are any number other than 0 and where A1 and A2 are heteroaromatic.
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).
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).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
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 34-40 are rejected under 35 U.S.C. 103 as being unpatentable over Nakano (JP 2002193796 A; English translation provided by Google Patents translate).
Nakano teaches an inflammatory factor activation inhibitor comprising a polysulfide derivative represented by any one of the following general formulas (I), (II) and (III) as an active
ingredient (p. 1, para. 1 under header “Claims (26)”). Formula (I) of Nakano is reproduced below (taken from p. 32 overall, p. (2) of original).
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Nakano further teaches a method of treating or preventing the following diseases, comprising administering the instantly claimed inflammatory factor activation inhibitors (claim 17, p. 3 overall, 4th paragraph from bottom of the page, lines 3-9): “conjunctivitis, choroiditis, parathyroidism, acne, alopecia, multiple sclerosis, transplantation, transplant rejection, autoimmune disease, adult respiratory distress syndrome, osteoarthritis, chronic joint Rheumatism, diabetes, diabetic neuropathy, diabetic nephropathy, diabetic cataract, atopic dermatitis, ileitis, ulcerative colitis, Crohn's disease, Asthma, psoriasis, periodontal disease, periodontitis, nephrosis, central nervous system demyelinating disease, glaucoma, cataract, macular degeneration…” (bolding added to emphasize eye diseases).
In a specific embodiment, Nakano teaches instantly claimed dimethyl 2,2'-dithiodi-benzoate as an inflammatory factor activation inhibitor (Table 3). The original Table 3 is reproduced below, with dimethyl 2,2'-dithiodi-benzoate highlighted in row 4 (heading “[Table 3]” in English translation on p. 19 overall under para. [0161]; original Table 3 found in p. 59 overall, top of p. (29) in original Japanese section).
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Nakano notes that “As shown in Tables 1 to 3, all of the inflammatory factor activation inhibitors of the present invention showed lower NF-κB activity at a lower concentration than pyrrolidinedithiocarbamate, which is a known NF-κB activation inhibitor. It is understood that the compound has an ability to inhibit the activation of inflammatory factor and has a high ability to inhibit the activation of the inflammatory factor” (p. 19 overall; para. [0162] in English translation).
Regarding claims 34-40, although Nakano does not explicitly teach administering a compound of instant formula 1 to treat an eye disease or disorder, it would have been prima facie obvious to do so. One would have been motivated and had a reasonable expectation of success to do so given Nakano teaches inflammatory factor inhibitors, including instantly claimed dimethyl 2,2'-dithiodi-benzoate, are useful in the treatment and prevention of cataract, conjunctivitis, glaucoma, and macular degeneration.
Taken all together, the teachings of Nakano would result in the invention of instant claims 34-40, with a reasonable expectation of success.
Conclusion
Claims 34-40 are rejected.
No claims are allowed.
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/O.D.H./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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