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 1-13 and 15-16 are pending.
Priority
Instant application 18/789,814, filed 07/31/2024 claims priority as follows:
PNG
media_image1.png
103
659
media_image1.png
Greyscale
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 02/25/2026 have been considered unless marked with a strikethrough.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
REQUIRED RESPONSE – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See the hyperlinks in the BACKGROUND INFORMATION section spanning pages 1-4 of the specification filed 07/31/2024.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
Claims 15-16 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.
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.
Breadth of the claims:
The claims are broadly directed to the use of any compound of claim 1 to treat a subject with any cancer, fibrotic disease, neurodegenerative disease, atherosclerosis, infection disease, or chronic kidney diseases. The breadth of the claims is substantial in view of the broad patient population scope encompassing many diseases
Nature of the invention:
The claims recite a method comprising administering compounds of Formula (I), disclosed as inhibitors of glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPTCL), to subjects having a variety of diseases including cancer, fibrotic diseases, neurodegenerative diseases, and infectious diseases.
State of the prior art and predictability in the art:
At the time of filing, the prior art showed that QPCT/L was recognized as a target with some in vivo and preclinical efficacy for specific indications such as atherosclerosis, CKD glomerulonephritis, NAFLD, and Alzheimer’s models. See, for example, COIMBRA (Expert Opinion on Therapeutic Patents, vol. 31, no. 9, Sept. 2021, pp. 809–36) and MOREIRA (Drug Discovery Today, vol. 28, no. 10, available online May 2023, p. 103644).
Coimbra provides a patent review of glutaminyl cyclase inhibitors ranging from 2004 to 2021. Coimbra discusses relevant pathologies starting at page 811 (Glutaminyl cyclase and pathologies), including Alzheimer’s disease, inflammatory processes, and cancer. While Coimbra identifies potential pathologies to be targeted by QPCT/L inhibitors, Coimbra also shows that the use of these compounds to treat the aforementioned diseases was in a nascent stage, with Alzheimer’s treatment being the most developed having only one inhibitor being tested in human clinical trials. For example, Coimbra notes 832 (Expert opinion, left side):
“Nevertheless, the translation of these inventions into therapeutic practice will require careful choices for the conditions targeted in clinical studies, with AD being the most promising field based on currently available data. To date, only one QC inhibitor (varoglutamstat) is being tested in human trials aiming to treat AD condition. Although it has shown promising preliminary results about safety and tolerability, as well as primary evidence of efficacy [120], it has not reached late clinical phases yet. Thus, further data on clinical evidence is needed to accurately validate QC as a target in this pathology. A related investigated strategy for AD treatment is to enhance pE-Aβ aggregates clearance. Quite recently, promising clinical evidence has shown that the administration of a monoclonal antibody directed against pE-Aβ called Donanemab (from Lilly) was generally well-tolerated, can reduce amyloid deposits in AD, and resulted in modestly less cognitive and functional decline than placebo [127,128].”
Moreira published 2 years after Coimbra and provides an overview of the therapeutic potential of QPCT/L inhibitors. The pathologies discussed in Moreira are consistent with those discussed in Coimbra (see Moreira, “Pathological and therapeutic perspective of QCs” starting at page 4). Yet similar to Coimbra, Moreira indicates that there is much to be done to actually identify which of these proposed diseases can actually be treated in humans with the QPCT/L inhibitors (see page 2, left side):
Hence, inhibiting QC activity might be a potential therapeutic strategy to treat pE-related diseases, such as Alzheimer’s disease (AD), synucleinopathies, Huntington’s disease (HD), periodontitis and related disorders, inflammatory diseases, and cancer. To date, several QPCT/L inhibitors have been designed and investigated in preclinical models of neurodegenerative, inflammatory, and oncological conditions, and one has reached clinical evaluation for AD.
In view of the state of the art identified above, the skilled artisan would be faced with a high degree of unpredictability in determining which patient populations inside of the enormous disease scope represented by claims 15 and 16 would actually benefit from administering the compounds of Formula (I) recited in claim 1.
Pharmacological activity in general is a very unpredictable area. Note also 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).
The specification itself describes the claimed compounds as having “unexpectedly” (i) potent inhibition of QPCT and QPCTL, (ii) potent inhibition of QPCT/L in particular cells (relevant to lung disease or cancer) and (iii) appropriate membrane permeability and a low in vitro efflux. Therefore applicant’s own characterization shows that the results of administering the claimed compounds to particular cell types could not have been predicted from the prior art and, by extension, the generalizability of this surprising result across different pathologies relating to different cell types cannot be predicted from the limited data presented.
Level of ordinary skill in the art:
The artisans using applicant’s method would hold an advanced degree in medicinal chemistry, oncology, pharmacology, and/or a related discipline, and possess several years of professional experience. While this person would possess a high level of skill, that skill would underscore the unpredictability of extending the specification’s results beyond the tested cell lines.
The amount of direction provided and working examples:
With respect to disease treatment scope, the specification provides a long speculative list of diseases starting at page 36 (“Method of treatment”). While the specification lists numerous diseases, it does not provide any actual evidence of the treatment of those diseases in a human subject.
The only working examples in the specification relate to QPCT/L inhibition (Assay A), CACO-2 permeability (Assay C), and an SIRPa signaling assay in Raji or A549 cell lines (Assay C, pages 29-31). The SIRPa signaling assay does not correlate any of the disclosed inhibition data (e.g. compound 7’s IC50 of 9 nM in Raji cells and 12 nM in A549 cells) with actual in vivo cancer treatment outcomes. There are no working examples relevant to the treatment of any other claimed disease (e.g. neurodegenerative disease, fibrotic disease, atherosclerosis, infectious disease, etc.).
See also 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 test each untested patient population (e.g. patients having specific cancer types, specific neurodegenerative diseases, specific fibrotic diseases, etc.) and assess if there is a benefit for that patient population after administering the claimed compounds. Each patient population would need to be independently tested, with no assurance that an actual improvement would be observed. Furthermore, diseases reading on the claims where it is currently unknown if QPCT/L activity drives the disease, the artisan would first need to determine if that is the case, and further identify if administration of the claimed compounds actually provides a benefit in a subject.
Therefore, in view of the factors discussed above, claims 15 and 16 are rejected as failing to comply with the enablement requirement.
Allowable Subject Matter
Claims 1-13 are allowed.
Close prior art is VEAL (WO 2024020517 A1; cited in IDS). Veal discloses QPCT/L inhibitors having the formula IC (page 35, top)
PNG
media_image2.png
208
200
media_image2.png
Greyscale
The closest compound disclosed by Veal to the instant claims is compound 133 (page 62):
PNG
media_image3.png
153
159
media_image3.png
Greyscale
.
Veal’s compound 133 satisfies nearly every requirement of Formula (I), but it is excluded from Formula (I) by the proviso recited in claim 1 which states: “with the proviso that R2 and R3 are not both H”.
In view of the aforementioned differences, Veal fails to anticipate claim 1. Moreover, the prior art fails to teach or suggest any compound of Formula (IC) in Veal having a piperidinyl ring substituted at the 2- or 6-position as required by instant claim 1. Further, the prior art fails to teach, suggest, or otherwise provide any motivation to select Veal’s compound 133 and modify it by replacing a hydrogen at the 2- or 6-position with an alkyl, fluoroalkyl, or cycloalkyl as required by the instant claims.
Therefore, in view of the foregoing, the compounds and compositions comprising said compounds recited in claims 1-13 are allowable.
Conclusion
Claims 1-13 are allowed. Claims 15-16 are rejected.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights