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 Claims
Claims 1, 3-10, and 12-15 are pending.
Priority
Instant application 18/283,855, filed 09/25/2023 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 09/25/2023, 09/24/2025, and 02/09/2026 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 05/28/2026 has been entered. Claims 1, 4, 6, 8, 12, 13, and 14 are amended. Claims 2 and 11 are cancelled.
Claims 1, 3, 5, 7, 9-10, and 12-15 were previously rejected under 35 U.S.C. 112(b) as indefinite. In view of the amendment to the claims, applicant has overcome the rejection. Therefore, the previous rejection under section 112(b) is withdrawn.
Claims 12-15 were previously rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. In view of the amendment to claim 12, applicant has overcome the rejection over claim 12. Therefore, the rejection of claim 12 under section 112(a) is withdrawn. However, the rejection of claims 13-15 is maintained. See the rejection and response to applicant’s Remarks further below.
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 13-15 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification, while being enabling for a method of inhibiting discoidin domain receptors, does not reasonably provide enablement for the treatment of fibrosis or any disease, disorder, or condition that involves fibrosis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice 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), the following factors are considered 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 the administration of compounds having Formula (I):
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to treat a disease, disorder or condition associated with dysregulation of discoidin domain receptors (DDRs). The compounds are disclosed as selective inhibitors of DDR1 and DDR2; particularly which can be administered by the inhalation route for respiratory disorders such as idiopathic pulmonary fibrosis (Specification, page 2, line 30 to page 3, line 4).
Breadth of the claims:
The claims are broadly directed to the use of the compounds for the treatment of all fibrosis or any disease, disorder, or condition that involves fibrosis, known today or that may be discovered in the future.
Level of ordinary skill in the art:
The artisans using applicant’s method would be a collaborative team of medicinal chemists, pharmacologists, and/or healthcare practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical arts, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
State of the prior art and predictability in the art:
With respect to the role of DDRs in disease recognized by the prior art, see for example Leitinger (“Discoidin Domain Receptor Functions in Physiological and Pathological Conditions.” International Review of Cell and Molecular Biology, vol. 310, 2014, pp. 39–87).
Leitinger is a review article summarizing the current knowledge of DDR-ligand interactions, DDR-initiated signal pathways and the molecular mechanisms that regulate receptor function (abstract). Also discussed are the roles of DDRs in development and disease progression (abstract). Leitinger states that both DDRs have been linked to a wide variety of human disorders, ranging from fibrotic disorders of different organs, atherosclerosis, arthritis and many types of cancers; targeted deletion of DDRs in mice and the use of a number of mouse models of chronic human diseases have helped to unravel DDR functions in disease progression; the DDRs usually play positive roles in pathologies, and the use of DDR inhibitors is therefore an attractive therapeutic approach, in particular for diseases that currently have limited treatment options (page 20, 2nd para.).
However, Leitinger states that the validation of the DDRs as drug targets is still incomplete. In particular, it is not clear for which diseases the DDR kinase activity is essential (page 25, last para.).
See also Guo et al. (“A Patent Review of Discoidin Domain Receptor 1 (DDR1) Modulators (2014-Present).” Expert Opinion on Therapeutic Patents, vol. 30, no. 5, May 2020, pp. 341–5; cited in IDS).
Guo is a review article summarizing current progress on the development of selective DDR1 modulators from 2014 to 2019. Guo discloses the closest prior art compounds to those instantly claimed in Fig. 5 (see compounds 10, 11, and 12):
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The compounds disclosed by Guo differ by (i) the tetrahydroisoquinoline or indane core, whereas the present claims require an indoline core; and (ii) the direct bond between the ring nitrogen and Hy, whereas the present claims require a linker L. However, while the above compounds show inhibitory activity for DDR1, Guo discloses that DDR1 inhibition is considered a new therapeutic strategy (page 348, 1st para.). Guo further discloses that there is still no subtype selective DDR1 inhibitor advanced for clinical investigation; and that further improvement of absorption, distribution, metabolism, and excretion (ADME) properties and various toxicities (T) of early DDR1 inhibitors is necessary (page 348, 2nd para.). Guo further states that given the fact that the pathological role of DDR1 is not yet understood, the new potent and selective inhibitors DDR1 inhibitors will serve as useful pharmacological tools to help the dissect its functions and lay the foundation for the development of DDR1 targeted therapies (page 348, last para.)
Therefore, while DDR1 and DDR2 were known in the prior art to be associated with many diverse human diseases, including fibrotic disorders, atherosclerosis, and cancer, etc; the prior art and the instant application does not provide a reasonable correlation between the inhibition of DDRs and the treatment of those diseases.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
That the claimed compounds can be used to treat or prevent all disorders associated with dysregulation of DDRs is an incredible finding for which Applicant has not provided sufficient supporting evidence.
The amount of direction provided and working examples:
The only direction or guidance present in the instant specification is the disclosure of diseases applicant considers as treatable by the claimed compounds, and experimental evidence demonstrating the inhibition of DDR1 and DDR2 with the claimed compounds. No experimental evidence (in vitro or in vivo) for the treatment of any disease is disclosed. No correlation between the inhibition of DDR1 and DDR2 and the treatment of any disease is disclosed.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine which disorders, of all the disorders potentially associated with dysregulation of DDRs, would actually be treated by the claimed compound.
A person having ordinary skill in the art at the time the invention was made would be faced with an undue amount of experimentation to use the compounds of Formula (I) according to the claimed method.
Therefore, claims 13-15 are rejected.
Response to Arguments
In the Remarks filed 05/28/2026, applicant points to pages 1-2 of the specification; and the Leitinger reference cited in the rejection; and states that these references “describe that the DDR receptor family have been linked to fibrotic disorders”. Applicant concludes therefore that claims 13 and 14 are fully enabled.
Applicant's arguments have been fully considered but they are not persuasive.
Claims 13-15 are drawn to the therapeutic treatment of diseases. Claim 13 is particularly broad because it encompasses fibrosis or any disease, disorder, or condition “that involves fibrosis”. Yet the specification provides no evidence correlating the inhibition of DDR with a therapeutic outcome in any fibrotic disease. See MPEP 2164.02 in this regard:
An in vitro or in vivo animal model example in the specification, in effect, constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute "working examples."
The examples in the specification are in vitro inhibitory binding assays (see pages 73-76 of the specification). While the specification provides working examples of DDR1 inhibition by the claimed compounds, it does not provide any evidence correlating the disclosed inhibitory activity with therapeutic treatment of any of the recited diseases. Without this correlation a person having ordinary skill would not know which patient populations would actually benefit from DDR1 inhibition.
Moreover, as noted in the rejection, the prior art established that at the time of filing there was still no subtype selective DDR1 inhibitor advanced for clinical investigation; and that further improvement of absorption, distribution, metabolism, and excretion (ADME) properties and various toxicities (T) of early DDR1 inhibitors was necessary (Guo, page 348, 2nd para.). And Leitinger, which applicant referred to in their Remarks, states “New roles for DDRs in disease progression have emerged in recent studies, but the validation of the DDRs as drug targets is still incomplete. In particular, it is not clear for which diseases the DDR kinase activity is essential.”
Applicant’s argument that “DDRs have been linked to fibrotic disorders” does not provide the reasonable correlation which is missing in the prior art and applicant’s disclosure: that inhibition of DDRs in a subject can actually treat fibrotic disorders.
Reconsidering the entire record, and weighing Applicant’s arguments together with the evidence in favor of a lack of enablement, the examiner finds that the rebuttal arguments do not outweigh the evidence supporting the rejection.
Therefore, in view of the foregoing, the rejection of claims 13-15 is maintained.
Allowable Subject Matter
Claims 1, 3-10, and 12 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
Guo (cited above) and Brekken (US 20180022730 A1) disclose the closest prior art compounds to those instantly claimed. See a comparison between the compounds in Guo/Brekken and those instantly claimed below:
Guo/Brekken
Instant Claims
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Example 1
The compounds disclosed by Guo and Brekken differ by (i) the tetrahydroisoquinoline or indane core, whereas the present claims require an indoline core; and (ii) the direct bond between the ring nitrogen and Hy, whereas the present claims require a linker L. The prior art fails to teach, suggest, or otherwise provide any motivation to modify Guo’s compounds in order to arrive at a compound instantly claimed.
Conclusion
Claims 13-15 are rejected. Claims 1, 3-10, and 12 are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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