DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restriction
2. Applicant’s election without traverse of Group I, claims 1-16, in the reply filed 03/20/2026 is acknowledged. Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. The requirement for species election is withdrawn and the search was expanded to encompass other exemplified compounds of formula (I).
Status of the claims
3. Claims 1-16 are pending. Claim 17 is withdrawn. Claims 1-16 are currently examined.
Priority
4. Acknowledgement is made of Applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to PCT/EP2022/064684 (filed 05/31/2022) which claims priority to EP 21177351.0 (filed 06/02/2021). The certified copy of the foreign application PCT/EP2022/064684 has been filed in the instant application on 12/01/2023.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 10/06/2023 and 03/20/2026 comply with the provisions of 37 CFR 1.97, 1.98, and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered on the merits. See attached copies of PTO-1449.
Claim Interpretation
Claims 9 and 11-13 recite “…wherein the AIID is driven by…” (e.g., a cytokine, Th1 cells, Th2 cells, Th17 cells, or cells of innate immune system), which is interpreted to be a property of the particular AIID envisioned by the Applicant. Therefore, if art is found to read on the method of claim 1, from which claims 9-13 depend, and an AIID, such as those recited in claim 10 (e.g., asthma), then it will also encompass all of the respective properties of the disease (e.g., being driven by Th2 cells).
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 1-16 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 the “delay of progression or treatment of an autoimmune and inflammatory disease”, does not reasonably provide enablement for “the prevention”. 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/or use the invention commensurate in scope with these claims.
As stated in MPEP § 2164.08, “The courts have 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’.” See also In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Here, the specification of the instant application 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. Namely, that a person of skill in the art, at the time of filing of the instant application, would not be enabled to use the methods as claimed to prevent the acquisition of an autoimmune and inflammatory disease with respect to the teachings of the instant disclosure without undue experimentation.
As stated in MPEP § 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”.”
The applicant’s attention is drawn to in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), where the court set forth eight factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. They are: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
It is noted that all of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
(A,B) The nature of the invention and the breadth of the claims: The claimed invention is directed to a method for treating an autoimmune and inflammatory disease in a subject, wherein the method is also for the “prevention…of an autoimmune and inflammatory disease.”
Examiner is interpreting the recitation of “prevention” of claim 1 and 16 to encompass preventing any and all autoimmune and inflammatory diseases before its acquisition in a subject, and thus the claimed scope is extremely broad with regards to the being treated.
(C,E) The state of the prior art and the predictability or lack thereof in the art: The state of the prior art in a field such as experimental therapeutics is such that it involves screening both in vitro and in vivo to determine whether a compound and method of using such compound exhibit the desired treatment of the desired disease. The state of the art teach that there is an urgent need for more disease and patient specific therapeutic strategies for autoimmune and inflammatory disease. For example, Fugger et al., “Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases” Cell, vol. 181:1, pgs 63-80, April 2020, DOI: 10.1016/j.cell.2020.03.007, describe “present therapies are broadly acting and non-disease specific; consequently, they are associated with numerous side effects” (see Abstract) and “the majority of patients are not responding optimally, if at all, to these therapies. Thus, there is a pressing need for development of new drugs or repositioning of drugs based on a molecular and clinical understanding of the specific autoimmune diseases in individual patients” (see Main text, para. 3). The existence of these obstacles established that the contemporary knowledge in the art would prevent one of ordinary skill from accepting any method of treatment on its face for the prevention of any and all autoimmune and inflammatory disease.
(F,G) The amount of direction provided and the presence of working examples:
Applicant provides examples of “Prophylactic treatment with 6-(4-tert-butylphenoxy)puridin-3-amine” in an humanized mouse model of Graft versus Host Disease (GvHD) following allo-bone marrow transplant (see pg. 83, line 8- pg. 84, line 4). However, Examiner also notes that 20% of 6-(4-tert-butylphenoxy)puridin-3-amine treated mice still developed GvHD (see pg. 83, lines 10-11; Figure 5) and in some cases only “led to a downregulation of cytokines implicated in GvHD pathophysiology (see pg. 83, lines16-17). Examiner The provided in vivo data are not examples of actually treating a disease in a patient suffering from GvHD. Rather, the suggestion of treatment by the method of the instant application is based on extrapolation of known mechanisms of the disease and the claimed compounds. Furthermore, this example of GvHD is the only in vivo example provided by the applicant of an autoimmune and inflammatory disease in the present disclosure. While mouse models are an acceptable model to study human disease and potential treatments, the lack of working examples that conclusively demonstrate prevention (i.e., prophylactic treatment) is a critical factor to be considered, especially where there is unpredictability of the art.
(D,H) The level of one of ordinary skill and the quantity of experimentation needed to make or use the invention based on the content of the disclosure: The relative skill of those in the art is high. However, that factor is outweighed 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).
Because of the known unpredictability of the art (as discussed in above) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that the claimed method would be capable of preventing the acquisition of all autoimmune and inflammatory disease.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent 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" (42 USPQ 2d 1001, Fed. Circuit 1997). A review of the state of the art fails to reveal that autoimmune and inflammatory disease arise from different mechanisms and that not all autoimmune and inflammatory disease respond to the same therapeutic intervention. Thus, in order to translate the suggestion in the instant disclosure to practice claimed methods with the full range of the claimed scope, one of skill in the art would have to undertake a novel and extensive research program across several subdisciplines (e.g., medicinal chemistry, biologics, autoimmunity, and tumor oncology, cardiovascular, hepatology, among others) to determine whether the methods of the claimed invention could successfully treat a patient suffering from said HIV-associated comorbidity.
Furthermore, in vivo and in vitro assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy. This is undue experimentation given the limited guidance and direction provided in the instant application.
Accordingly, the inventions of claims 1 and 16 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, 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.
Claim Rejections - 35 USC § 102
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
10. Claims 1-3, 9-12, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ma et al. "Effect of y-secretase Inhibitor on Th17 cell differentiation and function of mouse psoriasis-like skin inflammation," Journal of Translational Medicine, Vol. 16, March 10, 2018, pp. 1-10 (see IDS filed 06/05/2024) ("Ma et al.”).
12. Regarding claims 1-3, 9-13, and 16, Ma et al., teach the use of a TCM for treatment of psoriasis. Specifically, Ma et al., teach the “inhibitory effect of γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT) on Th17 cell differentiation and function in a mouse model of psoriasis-like skin inflammation” (see background, para. 3). Ma et al., further teach that “blocking Notch1 signaling by DAPT can result in a dose-dependent decrease of Th17 cell proportion, mRNA expression of Notch1, Hes-1, RORγt and IL-17A as well as IL-17A secretion in splenic CD4+ T cells” (see abstract; results, pg. 6; Figure 3c-d).
Examiner notes that claims 9 and 11-13, which depend from claim 1, are includes as properties of the AIID (i.e., psoriasis). Examiner further notes that, regarding claim 9, Ma et al., teach “Numerous studies have shown an increased expression of Th17 cells and IL-17A in psoriatic lesion and peripheral circulation and associated with the disease severity” (see background, para. 1) which reads on instant claim 9 that recites “wherein the AIID is driven by a cytokine selected from the group consisting of… IL-17” and regarding claims 10-12, Ma et al., teach that “distinct subtypes of CD4+ T cell, Th17 cells, have emerged as a key player in psoriasis pathogenesis, which are more highly expressed in psoriatic dermis” (see background, para. 1) which reads on instant claims 10-12 that recite “wherein the AIID is selected from the group consisting of… psoriasis” and “wherein the AIID is driven by … Thy17 cells and is psoriasis.”
15. Claims 1-4, 9-10, 12-13, and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by KleinJan et al., "The Notch pathway inhibitor stapled alpha-helical peptide derived from mastermind-like 1 (SAHM1) abrogates the hallmarks of allergic asthma", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol. 142, no. 1, July 2018, pages 76-85, XP002805695, ISSN: 0091-6749 (see IDS filed 06/05/2024) (“KleinJan et al.”).
Regarding claims 1-4, 10, and 16, KleinJan et al., teach the “targeting the active Notch transactivation complex by” using a TCM (i.e., hydrocarbon-stapled synthetic peptide stapled α-helical peptide derived from mastermind-like 1 (SAHM1)) in the house dust mite mouse model of allergic asthma (i.e., an AIID) (see Abstract). KleinJan disclose that “[s]upporting a critical role for Notch signaling in Th2 differentiation, we recently found that house dust mite (HDM)-driven allergic airway inflammation, Th2 activation, and [bronchial hyperactivity] were diminished in mice lacking the canonical Notch signaling mediator recombination signal-binding protein for IgJk region (RBPj) in T cells” (see Introduction, para. 2). KleinJan demonstrate that TCM treatment by SAHM1 administration reduced T cell numbers in bronchoalveolar lavage fluid (see Fig. 1, C and E). KleinJan further demonstrate that TCM treatment by SAHM1 administration reduced T-cell cytokine content (e.g., IL-5, IL-13, IL-17) (see Fig. 2, D).
Examiner notes that claims 9 and 12-13, which depend from claim 1, are includes as properties of the AIID (i.e., asthma). Examiner further notes that regarding claim 12, KleinJan et la., discloses that “the hallmarks of asthma are the direct consequences of enhanced activation of Th2 cells producing cytokines IL-4, IL-5, and IL-13 expression transcription factors (TF) Gata3 (see Introduction, para. 1).
Claim Rejections - 35 USC § 103
16. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
17. Claims 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al., as applied to claims 1-3, 9-12, and 16 as discussed above, and KleinJan et al., as applied to claims 1-4, 9-10, 12-13, and 16, respectively, and in further view of Radtke et al., (US 9,296,682 B2, March 3, 2016) (see IDS filed 06/05/2024).
18. Regarding claims 5-8, Ma et al., and KleinJan et al., do not teach the specific compound of Formula (I) as required by claims 5-8. However, in the same field of endeavor of development of novel compounds that are therapeutic inhibitors of the NOTCH signaling pathway, Radtke et al. teach “6-(4-(tert-butylphenoxy)pyridine-3-amine [compound] (13)… [and] pharmaceutical compositions comprising 6-(4-(tert-butylphenoxy)pyridine-3-amine (13) of Formula I, or one of its derivatives having Notch signaling pathway inhibition properties (see col. 1, lines 65-col. 2, line 19; col. 48, lines 44-54; compound shown below).
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Radtke et al., further teach that these compounds are “for use in the treatment and/or prevention of a cancer” (see col 2., lines 11-12).
One of skill in the art at the time of filing of the instant application would understand the current art of development and/or testing of novel Notch inhibitors across different therapeutic modalities (e.g., antibodies, small molecules) for autoimmune and inflammatory diseases according to the teachings of Ma et al., and KleinJan et al., and be motivated to substitute one known therapeutic Notch inhibitor (e.g., Notch inhibitors based on the teachings of Bauer) for the treatment of an autoimmune and inflammatory disease. See MPEP §2143 (I)(B).
Thus, claims 5-8 are obvious in view Ma et al., and KleinJan et al., and in further view of Radke et al.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Ma et al., as applied to claims 1-3, 9-12, and 16 as discussed above, and KleinJan et al., as applied to claims 1-4, 9-10, 12-13, and 16, respectively, and in further view of Ianni et al., “NOTCH and Graft-Versus-Host Disease”, Front. Immunol. Vol. 9:1825, August 2018, doi: 10.3389/fimmu.2018.01825.
Regarding claims 14-15, Ma et al. and KleinJan et al., differ from the instant claimed invention in they do not explicitly teach method of claim 1 is applied to the AIID graft-versus-host disease.
However, in the same field of endeavor of Notch signaling in autoimmune and inflammatory disease, Ianni et al., teach that “T cells play a key role in the development of graft-versus-host disease (GvHD). NOTCH pathway is a conserved signal transduction system that regulates T cell development and differentiation” (see Abstract) and “NOTCH signaling has emerged as a new regulator of acute and c[hronic]GvHD” (see Ianni et al., Introduction, para.4). Similarly, as discussed above, Ma et al., and KleinJan et al., teach that T cells and Notch signaling contribute to the etiology of psoriasis and allergic asthma, respectively, as discussed above.
Thus, it would have been prima facie obvious to try the method of treating an autoimmune and inflammatory disease with a TCM based on the teachings of Ma et al., and KleinJan et al., because all of the AIIDs disclosed therein share a mechanism of action (i.e., are modulated by T cells and Notch signaling) with a reasonable expectation of success (see MPEP §2143 (I)(E)).
Thus claims 14-15 would be obvious over Ma et al., and KleinJan et al., and in further view of Ianni et al.
Conclusion
20. No claims are allowed in this action.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALAN JEROME FOWLER whose telephone number is (571)272-0195. The examiner can normally be reached Monday - Friday 9-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALAN J FOWLER/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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