DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-9, 15, 17, 18, 20, 24-28, 36 and 37 are pending in the instant invention. According to the Amendments to the Claims, filed November 3, 2025, claims 10-14, 16, 19, 21-23, 29-35 and 38-44 were cancelled.
Status of Priority
This invention is a Continuation (CON) of International Application No. PCT/EP2021/081081, filed November 9, 2021, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application No. 63/112,498, filed November 11, 2020.
Restrictions / Election of Species
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The inventor’s or joint inventor’s provisional election of the following, with traverse, in the reply filed on November 3, 2025, is acknowledged: a) Group I - claims 1-4, 15 and 17; and b) substituted pyrrolo[3,2-c]pyridine of formula (I) - pp. 109-110, Example 2, shown to the right below, and hereafter referred to as N-(2-((4-(3-((3-fluoro-2-methylphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]-pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide, where R1 = -CH3; R2 = -F; R3 = -H; R4 = -H; R5 = -H; and R6 = -CH2CH2NR7C(O)CH=CH2, wherein R7 = -H. Claims 1-4, 15 and 17 read on the elected species. Affirmation of this election must be made by the inventor or joint inventor in replying to this Office action.
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Similarly, the inventor or joint inventor should further note that the traversal is on the grounds that the Examiner has not established that there would be a serious search and examination burden. This is not found persuasive because the multiple inventions in the instant invention are independent or distinct for the reasons disclosed in the Requirement for Restriction / Election of Species, mailed on September 4, 2025.
Likewise, the inventor or joint inventor should further note that there would be a serious burden on the examiner if restriction was not required because the inventions have acquired a separate status in the art due to their divergent subject matter and would require a different field of search.
Next, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL.
Then, the inventor or joint inventor should further note that the elected species, shown to the right above, was found to be free of the prior art.
Moreover, the inventor or joint inventor should further note that claims 5-9, 18, 20, 24-28, 36 and 37 were withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to a nonelected or cancelled invention, there being no allowable generic or linking claim.
Thus, a first Office action and prosecution on the merits of claims 1-4, 15 and 17 is contained within.
Specification Objection - Disclosure
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the inventor’s or joint inventor’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility invention should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase Not Applicable should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A
COMPACT DISC.
(f) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art (including information disclosed under 37 CFR 1.97
and 1.98).
(g) BRIEF SUMMARY OF THE INVENTION.
(h) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(i) DETAILED DESCRIPTION OF THE INVENTION.
(j) CLAIM OR CLAIMS (commencing on a separate sheet).
(k) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(l) SEQUENCE LISTING (See MPEP § 2424 and 37 CFR 1.821-1.825).
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(b) above and 37 CFR 1.77(c). Revisions should particularly include and/or address: a) section headings (b-i), where applicable; and b) bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation:
A compound of formula (I):
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(I)
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 represents H, Cl, Br, CN, CH3, CF3, CH2CH3, CH2CHF2, OCH3, or OCHF2;
R2 represents H, F, Cl, Br, CH3, or CH2CH3;
R3 represents H or F;
R4 represents H, CH3, or CF3;
R5 represents H, CH3, or CF3; or
R4 and R5, together with the carbon atom to which they are attached, represent a C3-C6 cycloalkyl;
R6 represents:
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, or
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; and
R7 represents H or CH3.
Appropriate correction is required. See MPEP § 2173.02.
Claim 2 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R1 represents H, CH3, OCH3, or OCHF2;
R2 represents H, F, or Cl;
R4 represents H or CH3;
R5 represents H or CH3; or
R4 and R5, together with the carbon atom to which they are attached, represent a C3-C5 cycloalkyl; and
R6 represents:
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, or
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 3 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R1 represents CH3, OCH3, or OCHF2;
R2 represents H, F, or Cl;
R3 represents H;
R4 represents H or CH3;
R5 represents H or CH3; or
R4 and R5, together with the carbon atom to which they are attached, represent a cyclobutyl; and
R6 represents:
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, or
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.
Appropriate correction is required. See MPEP § 2173.02.
Claim 4 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The compound according to claim 1, or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
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,
or a pharmaceutically acceptable salt or tautomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 15 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
A pharmaceutical composition comprising at least one pharmaceutically acceptable auxiliary together with at least one compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 17 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
A combination comprising at least one compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and at least one additional active ingredient selected from the group consisting of a chemotherapeutic anti-cancer agent and a target-specific anti-cancer agent.
Appropriate correction is required. See MPEP § 2173.02.
Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I)
Claims 1-3 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for substituted pyrrolo[3,2-c]pyridines of the formula (I), does not reasonably provide enablement for N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I). 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. N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I), as recited in claims 1-3, respectively, have not been adequately enabled in the specification to allow any person having ordinary skill in the art, at the time this invention was made, to make and/or use N-oxides, of substituted pyrrolo[3,2-c]pyridines of the formula (I).
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. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the instant invention, are summarized as follows:
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(a) Breadth of the claims - the breadth of the claims includes substituted pyrrolo[3,2-c]-pyridines of the formula (I), shown to the right below, as well as the myriad of potential N-oxides formulated from these substituted pyrrolo[3,2-c]pyridines of the formula (I), shown to the right, respectively;
(b) Nature of the invention - the nature of the invention is evaluation of substituted pyrrolo[3,2-c]pyridines of the formula (I), shown to the right above, and/or N-oxides thereof, and the pharmacokinetic behavior of these substances as epidermal growth factor receptor (EGFR) inhibitors;
(c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Moreover, US 2023/0364070 provides a synthesis of the instantly recited substituted pyrrolo[3,2-c]pyridines of the formula (I) {Milgram, et al. US 2023/0364070, 2023};
(d) Level of one of ordinary skill in the art - the artisans synthesizing the inventor’s or joint inventor’s substituted pyrrolo[3,2-c]pyridines of the formula (I), and/or N-oxides thereof, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is unclear based on the combination of the instant specification, and Milgram, et al. in US 2023/0364070, whether the instantly recited N-oxides of substituted pyrrolo[3,2-c]-pyridines of the formula (I) are enabled. Moreover, the following excerpt is taken from Dörwald, which has relevance to the synthesis of N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I) {Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA, 2005, Preface}:
Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why.
Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work.
Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious).
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I);
(g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use substituted pyrrolo[3,2-c]pyridines of the formula (I); however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the instantly recited N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I). The specification lacks working examples of N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I).
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure - predicting whether a recited compound, and/or an N-oxide thereof, is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper
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guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Similarly, the specification, as originally filed, including any references incorporated therein, fails to provide the necessary support required by 35 U.S.C. § 112(a) to enable the instantly recited N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I). Thus, it is unclear, based on the guidance provided by the specification, whether an N-oxide of a substituted pyrrolo[3,2-c]pyridine of the formula (I), such as 3-(2-acrylamidoethoxy)-4-(3-((3-fluoro-2-methylphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyridine 1-oxide, shown to the left above, is either synthetically feasible or possesses utility as an epidermal growth factor receptor (EGFR) inhibitor.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using N-oxides of substituted pyrrolo[3,2-c]pyridines of the formula (I), is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 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)(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 1-3 and 15 are rejected under 35 U.S.C. § 102(a)(2) as being anticipated by Milgram, et al. in US 2023/0364070.
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The inventor or joint inventor should note that the instant invention recites a substituted pyrrolo[3,2-c]pyridine of the formula (I), shown to the left, where R1 = -CH3; R2 = -F; R3 = -H; R4 = -H; R5 = -H; and R6 = -CH2-(1-acryloylpyrrolidin-2-yl), respectively, and/or a pharmaceutical composition thereof, as an epidermal growth factor receptor (EGFR) inhibitor.
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Similarly, the inventor or joint inventor should further note that Milgram, et al. (US 2023/0364070) teaches a substituted pyrrolo[3,2-c]pyridine of the formula (I), shown to the right, where R1 = -CH3; R2 = -F; R3 = -H; R4 = -H; R5 = -H; and R6 = -CH2-(1-acryloylpyrrolidin-2-yl), respectively, and/or a pharmaceutical composition thereof, as an epidermal growth factor receptor (EGFR) inhibitor {p. 60, Compound #140; p. 276, Example 9, Compound 140; 63/082234 - p. 171, Example 9, Compound 140; and pharmaceutical compositions - p. 5, ¶[0113]}.
Likewise, the inventor or joint inventor should further note that, although not explicitly discussed herein, this reference contains additional species that may anticipate the instantly recited substituted pyrrolo[3,2-c]pyridines of the formula (I). Consequently, any amendments to the claims and/or arguments formulated to overcome rejections rendered under 35 U.S.C. § 102 should address this reference as a whole and should not be limited to the species discussed or disclosed explicitly herein.
Moreover, the inventor or joint inventor should further note that in the event the determination of the status of the invention as subject to AIA 35 U.S.C. § 102 (or as subject to pre-AIA 35 U.S.C. § 102) is incorrect, any correction of the statutory basis for the instant 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.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624