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 .
Claim of Foreign Priority
Applicant’s claim of foreign priority and Certified Copy of Foreign Priority document are acknowledged.
Status of the Claims
Claims 1-18 are pending and examined.
Claim Rejections - 35 USC § 112
Claims 1-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 refers to “Salts of a compound…” It would appear that Applicant intends to claim individual salt forms rather than only multiple salts. The examiner suggests Applicant change claim 1 to start with the phrase “A salt form of a compound of formula (I), wherein the salt form is selected from….”
Further dependent claims can be amended to recite, e.g.: “A salt form of claim 1, wherein the salt form….”
Further, dependent claims 2-18, e.g., refer to the salts and hydrates thereof (in the plural) according to claim 1, wherein the salt (in the singular) is….This should be amended to be consistent. It remains unclear if Applicant is intending to claim a salt or multiple salts.
Claims 2 and 3 use the term “preferably” and it is not if a preference is required by the claims.
Claims 4, 8, and 12 include phrases in parenthesis. These phrases appear to further limit the claims. The examiner notes that Applicant can claim “the adipate is crystalline form B” to clarify.
Claims 17 and 18 refer to treating but do not require a subject in need thereof. It is not clear if a subject is required to have a claimed condition. Applicant should add the language to a subject in need thereof to the claims if Applicant intends to claim administration to a subject that has a claimed condition.
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 1-3, 16, 17, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over LÖNN et al., (WO2015/110826), in view of Berge et al., “Journal of Pharmaceutical Sciences,” January 1977 Volume 66, Number 1, and in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem Rev 1996, 96, 3147-3176.
LÖNN teaches DPP1 inhibitor compounds for use in treating conditions such as respiratory disease including asthma, COPD, and others. See Abstract. The compound has the following formula (I).
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279
448
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. Further, R1 can be the following:
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165
202
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wherein R7 is fluorine or hydrogen; R6 is methyl; and X is oxygen. In such instances, the distinction over the claimed compound is a single fluorine substituted for a hydrogen (when R7 is hydrogen) or it is an isomer (when R7 is fluorine). According to M.P.E.P. § 2144.09, a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963). Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or 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).
Further, LÖNN teaches conventional techniques can be used to separate tautomers, including fractional crystallization. Crystallization techniques were employed throughout. See Example 2. A mandelate salt was formed through crystallization.
Salt forms that are contemplated by the prior art are relatively unlimited. “Where the compound of formula (I) is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g. Na or K, an alkali earth metal salt, e.g. Ca or Mg, or an organic amine salt. Where the compound of formula (I) is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.”
Berge et al., “Journal of Pharmaceutical Sciences,” January 1977 Volume 66, Number 1, cited by LÖNN teaches the most common anion salts including hydrobromide, maleate, hydrochloride, fumarate, adipate, benzoate, citrate, malate, and others claimed. See Tables 1 and 2.
Patani teaches the common use and substitution of a hydrogen with a fluorine. There are numerous examples in which such substitution has worked and a basis for this is similar steric parameters and van der Waal’s radii being similar. See p3149, 4th full par.
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 in view of LÖNN, Berge, and Patani. One would be motivated to do so because the claimed compound is known as a DPP1 inhibitor for treating claimed conditions and salt forms are taught. Further, crystalline forms are also taught. The distinction over the prior art is either: a single hydrogen substituted with a fluorine or an isomer as fluorine is taught in a different position on a compound wherein the position of the fluorine is the single difference in structure. Isomers for a same purpose are obvious variants and the substitution of a fluorine for a hydrogen is among the most commonly employed bioisosteric substitutions for rational drug design with a reasonable and predictable expectation of success. This is particularly the case when the prior art teaches compounds to have DPP1 inhibitory activity when a fluorine is positioned in other locations of a similar core structure.
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 17 and 18 rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating specific respiratory conditions, including asthma and COPD, is not enabled for all subjects with a condition “mediated by DPP1,” such as NSCLC, e.g. The examiner interprets the phrase “acute lung injury” of claim 18 to include cancer, trauma, and any cause of such injury. Further, there is no approval for the treatment of cystic fibrosis bronchiectasis to be treated with a DPP1 inhibitor.
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. Prevention of diseases nor treatment of claimed conditions, including those “mediated by DPP1.” Conditions mediated by DPP1 can include cystic fibrosis, autoimmune conditions, congenital diseases, and others in which neutrophils play a role in inflammation. While potential for treatment exists, it is not clear that such treatment works in all conditions including colorectal cancer, e.g. Many cancers, e.g., are DPP1 mediated. Kim et al., “Cathepsin C regulates tumor progression via the Yes-associated protein signaling pathway in non-small cell lung cancer,” Am J Cancer Res 2024;14(1):97-113, teaches a role of DPP1 in various cancers, including liver and breast has been reported, its role in NSCLC was not yet known.
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 DPP1 mediated conditions.
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.”
Kim et al., “Cathepsin C regulates tumor progression via the Yes-associated protein signaling pathway in non-small cell lung cancer,” Am J Cancer Res 2024;14(1):97-113, teaches a role of DPP1 in various cancers, including liver and breast has been reported, its role in NSCLC was not yet known.
Wexler, Experimental anti-inflammatory brensocatib tolerated well in study,” https://cysticfibrosisnewstoday.com/news/experimental-anti-inflammatory-therapy-brensocatib-tolerated-well-study/ (date accessed June 17, 2026), published October 2, 2025, indicates that the DPP1 inflammation is not approved for treating cystic fibrosis.
Thus, the state of the art indicates that DPP1 is associated with a neutrophil-directed inflammatory response. Such response is common in a vast breadth of conditions including cancers, autoimmune conditions, NSCLC, cystic fibrosis and others. However, drugs that are approved as DPP1 inhibitors are not yet approved to treat cancers, cystic fibrosis, and other claimed conditions.
As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to treat conditions mediated by DPP1. 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.
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.
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 provides an assay showing that the claimed compound will inhibit DPP1 activity. See Example 1. Further, Example 2 measures pharmacokinetic data for a small group of rats. The data was for a dose of 0.2 and 0.3 mg administered through gavage and via IV administration. The conclusion is that the compound has “good” bioavailability and PK characteristics. Se p71. Finally, toxicity was measured to show that the claimed compound is less toxic than INS1007, which is brensocatib. Brensocatib appears to be the claimed compound without a fluorine atom. This is the compound taught by the cited prior art. See LÖNN et al.
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 inhibit DPP1. Considering that the conditions claimed include any condition mediated by DPP1, which includes numerous cancers, autoimmune conditions, cystic fibrosis, and acute lung injury of any source, claims 17 and 18 are broad. Yet, as discussed above, the instant Specification does not provide any examples in which a claimed compound can treat a condition. There is no data or showing that the claimed compound can treat liver, breast, or lung cancer, cystic fibrosis, or a vast breadth of autoimmune conditions.
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. While potential to treat numerous conditions may exist, there does not appear to be any showing in the art that the claimed compound, even if effective at inhibiting DPP1, would have a reasonable expectation of success in treating numerous conditions that are considered to be mediated by DPP1.
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 hundreds of millions of compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure of 188 compounds comprising discrepancies in activity when combined with the vast potential conditions to be prevented and treated. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known 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.
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 the prevention and treatment of claimed conditions. To treat claimed conditions, 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 DPP1 mediated 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 16-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,807,635. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘635 patent are directed to the claimed compound, stereoisomers, and salts thereof. Further, methods of treating claimed diseases is also claimed in claim 8 of the ‘635 patent.
Claims 1-3 and 16-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. 12,365,673. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘673 patent are directed to the claimed compound, stereoisomers, and salts thereof. Further, methods of treating claimed diseases is also claimed in claim 6 of the ‘673 patent.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/840,748. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘748 application are directed to making the claimed compound, salts thereof, crystal forms thereof, and provides methods of synthesis that can yield a claimed polymorph.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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
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