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 .
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.
Status of the Claims
Claims 1-10 are pending and examined.
Claim Objections
Applicant is advised that should claim 9 be found allowable, claim 10 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Further, the language in claim 9 “effective dose of a compound is represented” should state: “a therapeutically effective dose of a compound represented by formula (I).” Consideration of clearer language is requested.
Claim Rejections - 35 USC § 112
Claim 3 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 3 refers to “pain” as a skin disorder. Claim 3 also refers to “wound” and “lesion” and “ulcer.” It is not clear if the pain, wound, lesion, and ulcer, e.g., are skin pain and/or skin wounds or if Applicant is asserting that pain and wounds are generically skin conditions. It is also not clear if the location of pain and/or ulcer must be the skin or if such symptom can be a symptom of condition that also impacts the skin but constitutes an ulcer or wound or pain in another region of the body. Clarification is requested. Applicant can overcome this by stating that a symptom of a skin disorder is pain or a wound associated with the skin, e.g., should support exist in the instant Specification.
Claim Rejections - 35 USC § 112
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 1-8 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 acne and atopic dermatitis, does not reasonably provide enablement for all skin conditions, including conditions listed in claim 3, including pain, ulcer, sebaceous carcinoma, Merkel cell carcinoma, and other conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims. With further regard to claim 2, it is not clear that the claimed agents treat upregulated and downregulated (i.e., dysregulated) CXCL1, TNFalpha, and IL1alpha. Benzamil, e.g., has only been shown to treat overexpression CXCL1 and TNFalpha and not dysregulation generally. See instant claim 2.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to treat all skin disorders, which are inclusive of skin cancers, pain, wound, and many other disparate conditions such as Familial mediterranean fever, ulcer, lesion, and others. The invention also includes treating Still’s disease and a number of conditions, which would not appear to be considered skin disorders by a POSA.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to reduce expression of CXCL1, TNFalpha, and IL1alpha. See Figures 3, 4, and 5. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case. For example, comparing the structures of those compounds 1-73 (of claim 40, e.g.), they appear relatively similar. However, the in vitro IC50 ERAP1 inhibitory data show substantial differences in in vitro efficacy. Thus, each change in structure must be evaluated for drastic changes in efficacy.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification disclosed in silico experimentation on ion channels and conditions such as acne in which CXCL1 and IL1-alpha are upregulated. See Spec. @ p16, 1st par. Similarly, Figure 2a shows that CXCL1 and TNF-alpha are upregulated in patients with atopic dermatitis. See p16, 2nd par.
Benzamil was the only compound tested and reduced the expression of CXCL1, IL1a, and TNFa. It was shown to prevent specific proinflammatory signaling as described, citing Figures 1 and 2. See p17, last par. Of the conditions described in the Figures, only acne and atopic dermatitis are mentioned. Further, only inhibition of CXCL1, IL1a, and TNFa are described.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
As to the first inquiry, as discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification as an inhibitor of CXCL1, IL1a, and TNFa. Considering that the conditions claimed include conditions including pain, ulcer, wound, multiple forms of cancers, and rare diseases, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses only a single compound and in silico data for acne and atopic dermatitis. Despite the variability in efficacy and the lack of an any in vivo assay, there instant claims are directed to treating and preventing a vast number of distinct conditions. The following conditions are claimed in the narrowed dependent claim 3:
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As such, the claims are broad with respect to the disclosure. The second inquiry is discussed in detail below. With respect to a subject population, there is not a single example of a disease treated or an in vivo model in which the claimed compounds have been tested. There are only 2 conditions treated with a single compound. That compound is benzamil. All experiments were performed in silico.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to inhibit CXCL1, IL1a, and TNFa. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of unrelated conditions claimed to be treated and the lack of any in vivo experimental data. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the vast conditions claimed can be treated. Although the skilled artisan would have known that certain conditions known to be treated by similarly active compounds, the skilled artisan would have also known that the treatment of distinct conditions is not always predictable.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to definitively determine the specific population of individuals who would need to be treated and would furthermore have to determine which of the claimed compounds would provide for treatment and identify a required dosage and route of administration. To treat cancer, e.g., and immune conditions in any patient population, as the instant claims are drawn to, would require undue experimentation to both develop an animal model which would reasonably correlate with all forms of “skin” conditions and also to identify the portion of the population in which the instantly claimed compounds would need to necessarily be administered.
Thus, factors such as "sufficient working examples", "the level of skill in the art" and "predictability", etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claim, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
The court in Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure. This can include treating conditions by inhibiting the overexpression of CXCL1, e.g., and those conditions should be shown or established as being treatable through such inhibition.
Claim Rejections - 35 USC § 102
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.
Claims 1-7, 9, and 10 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Xu et al., (US2015/0065431) (cited in ISR).
Xu teaches compositions for treating skin conditions including dermatitis and others. See Abstract. In one embodiment the API is an epidermal sodium channel (ENac) inhibitor. See par. 17. The ENac inhibitor can be benzamil, among a limited list of agents. See par.’s 20, 40, as well as prior art claims 4 and 12. The compositions can comprise a topical component including a cream, ointment, or gel. See Abstract and par. 16. The methods of Xu include treating conditions such as eczema, seborrheic dermatitis, and others. See par. 14. As evidenced by the Specification, both of these conditions are those in which CXCL1 and TNFa are upregulated. Subjects are human and non-human. The composition can comprise one or excipients or diluents. See par. 55.
As such, claims 1-7, 9, and 10 are anticipated by the prior art.
Claims 1-7, 9, and 10 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Warren et al., (US2022/0062379) (filed January 17, 2020).
Warren teaches a method for treating immune dysregulation by administering a therapeutically effective amount of benzamil. See prior art claims 76 and 79. Further, the condition can be a dermatologic condition including eczema, dermatitis, vitiligo, and others. See prior art claim 83. Administration can be topically. See par. 39. Treatment can be a human or non-human. Further, administration can be systemic or local. See par. 40. As evidenced by the Specification, these conditions include those in which CXCL1 and TNFa are upregulated. For topical administration the dosage can be in the form of a cream, lotion, ointment, or gel. See par. 39.
Claims 76, 79, and 81-83 are shown below.
76. A method for treating a disease of immune dysregulation in a subject, said method comprising administering to the subject a therapeutically effective amount of a gliptin, benzamil, or ISA2011B.
79. The method of claim 76, wherein benzamil is administered.
81. The method of claim 76, wherein the disease of immune dysregulation is an inflammatory disease.
82. The method of claim 81, wherein the inflammatory disease is a dermatological disorder.
83. The method of claim 82, wherein the dermatological disorder is atopic dermatitis, alopecia areata, bulloid pemphigus, chronic eczema, dermatomyositis, erythema nodosum, epidermolysis bullosa, hydradenitis suppurativa, lichen planus, pemphigus vulgaris, psoriasis, pyoderma gangrenosum, scleroderma, or vitiligo.
As such, claims 1-7, 9, and 10 are anticipated by the prior art.
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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al., (US2015/0065431) (cited in ISR).
Xu teaches compositions for treating skin conditions including dermatitis and others. See Abstract. In one embodiment the API is an epidermal sodium channel (ENac) inhibitor. See par. 17. The ENac inhibitor can be benzamil, among a limited list of agents. See par.’s 20, 40, as well as prior art claims 4 and 12. The compositions can comprise a topical component including a cream, ointment, or gel. See Abstract and par. 16. The methods of Xu include treating conditions such as eczema, seborrheic dermatitis, and others. See par. 14. As evidenced by the Specification, both of these conditions are those in which CXCL1 and TNFa are upregulated. Subjects are human and non-human. The composition can comprise one or excipients or diluents. See par. 55.
With regard to claim 8, the examiner notes that an amount of a known result-effective variable would be optimized to achieve a desired therapeutic effect. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods and products in view of the teachings of Xu. One would be motivated to optimize the concentration of a known result-effective variable through nothing more than routine experimentation and arrive at administering a dosage in a claimed form and route of administration that yields a claimed serum concentration. One can do so with a reasonable and predictable expectation of success. As such, no claim is allowed.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Warren et al., (US2022/0062379) (filed January 17, 2020).
Warren teaches a method for treating immune dysregulation by administering a therapeutically effective amount of benzamil. See prior art claims 76 and 79. Further, the condition can be a dermatologic condition including eczema, dermatitis, vitiligo, and others. See prior art claim 83. Administration can be topically. See par. 39. Treatment can be a human or non-human. Further, administration can be systemic or local. See par. 40. As evidenced by the Specification, these conditions include those in which CXCL1 and TNFa are upregulated.
Claims 76, 79, and 81-83 are shown below.
76. A method for treating a disease of immune dysregulation in a subject, said method comprising administering to the subject a therapeutically effective amount of a gliptin, benzamil, or ISA2011B.
79. The method of claim 76, wherein benzamil is administered.
81. The method of claim 76, wherein the disease of immune dysregulation is an inflammatory disease.
82. The method of claim 81, wherein the inflammatory disease is a dermatological disorder.
83. The method of claim 82, wherein the dermatological disorder is atopic dermatitis, alopecia areata, bulloid pemphigus, chronic eczema, dermatomyositis, erythema nodosum, epidermolysis bullosa, hydradenitis suppurativa, lichen planus, pemphigus vulgaris, psoriasis, pyoderma gangrenosum, scleroderma, or vitiligo.
With regard to claim 8, the examiner notes that an amount of a known result-effective variable would be optimized to achieve a desired therapeutic effect. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985); and generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
It would have been prima facie obvious to a person having ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods and products in view of the teachings of Warren. One would be motivated to optimize the concentration of a known result-effective variable through nothing more than routine experimentation and arrive at administering a dosage in a claimed form and route of administration that yields a claimed serum concentration. One can do so with a reasonable and predictable expectation of success.
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 L. 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