DETAILED ACTION
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 the Claims and Response to Amendments
The amendments filed on March 6, 2026 have been acknowledged and entered. Claims 51-65 are pending. Claims 57-63 were previously withdrawn, but are now rejoined (see “Election/Restrictions” section below). Claims 1-50 are cancelled.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this office action has been withdrawn or rendered moot in view of applicant’s amendments and/or remarks.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2021/053368, filed on October 4, 2021. This application also claims the benefits of U.S. Provisional Application No. 63/087,517, filed on October 5, 2020 and 63/232,450, filed on August 12, 2021.
Election/Restrictions
Claims 51-56, 64, and 65 are allowable. Claims 57-63, previously withdrawn from consideration as a result of a restriction requirement, require all the limitations of an allowable claim. Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement among inventions I and II, as set forth in the Office action mailed on September 5, 2025, is hereby withdrawn and claims 57-63 are hereby rejoined and fully examined for patentability under 37 CFR 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
In summary, claims 57-63 are rejoined; claims 51-65 are currently pending.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Kawai et al. (Kawai) (CA 2997051 A1; published March 9, 2017).
Novelty:
Kawai teaches pyrazolo[3,4-d]pyrimidine derivatives of the formula (I):
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(herein, referred to as Kawai-formula-I)
as compounds having an HER2 inhibitory action and a suppressive effect on cell proliferation (abstract). The variables of Kawai-formula-I are defined in claim 1 of Kawai. The HER2 inhibitors disclosed in Kawai differ from those presently claimed as explained below:
In Kawai, the phenyl ring must be linked to NR2R3 (wherein NR2R3 can be a 4- to 8-membered nitrogen-containing saturated heterocyclic group; see Kawai, pg. 226, last 7 lines of claim 1) via the -W-(C=O)- linker (wherein W is -CH2-, -O-, or -NH-).
In the instant case, the phenyl ring must be linked to the A-ring (a fused-heterobicyclyl or 5-membered heterocyclyl) either directly (i.e., no linker group = X linker is absent) or via an X linker (wherein X is -CH2-, -O-, or –(C=O)-).
Since the linker group in Kawai is different than the linker group in the instant case (-W-(C=O)- vs. X, respectively), the HER2 inhibitors disclosed in Kawai, therefore, have structures that do not overlap with those of the instant compounds and the instant invention is considered novel.
Nonobviousness:
Both Kawai and the present invention disclose HER2 inhibitors. Although a POSITA would have considered it obvious to further explore derivatives of the compounds disclosed in Kawai (such as the compounds of the present invention) as HER2 inhibitors, Kawai does not teach nor suggest:
modifying the -W-(C=O)- linker of Kawai-formula-I to be -CH2-, -O-, or –(C=O)- OR
completely removing the -W-(C=O)- linker of Kawai-formula-I
to arrive at the instantly claimed compounds.
For example, compound 71 of Kawai has the following structure (pg. 215):
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.
If there was no -CH2- between the phenyl ring and –(C=O)-pyrrolidinyl group, then the resulting compound would be encompassed by instant claim 51. However, Kawai does not teach nor suggest the removal of -CH2- from the -W-(C=O)- linker.
Thus, the instant invention is considered nonobvious.
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 57-63 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.
As stated in the 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.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims a compound of Formula I:
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, a pharmaceutically acceptable salt, and a stereoisomer thereof useful as an inhibitor of HER2 for the treatment of disorders and diseases associated with HER2, such as cancer.
The variables of Formula I are defined in instant claim 51.
State of the prior art
See “Examiner’s note on novelty and nonobviousness” section above.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples
The instant specification only provides limited in vitro data demonstrating HER2 inhibitor activity of a small subset of the instantly claimed compounds in Ba/F3 cells using MTS assays (see instant Example 4).
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
Ba/F3 cells, a murine interleukin-3 dependent pro-B cell line, is a model system commonly used to assess the ability of small-molecule kinase inhibitors to inhibit kinase activity in vitro (see Warmuth, M. et al. Curr Opin Oncol 2007, 19, 55-60; pg. 55, left col., “Recent Findings” section in gray box). However, the mere demonstration that a compound inhibits kinase activity in such an assay system does not establish that the compound is effective for treating any disease or disorder characterized or mediated by aberrant human epidermal growth factor receptor 2 (HER2) activity.
The claims encompass a broad range of diseases and disorders, including any cancer and specific subtypes of cancer such as non-small cell lung cancer (NSCLC). The specification, however, provides only limited in vitro data demonstrating HER2 inhibitor activity of a small number of the instantly claimed compounds in Ba/F3 cells. The specification does not provide any in vivo data, disease-relevant cellular models, or other evidence demonstrating that the disclosed compounds are effective in treating any of the recited diseases, including any cancer.
The specification further does not establish a reasonable correlation between inhibition of HER2 activity in Ba/F3 cells using the novel and nonobvious compounds of the instant application and therapeutic efficacy across the full scope of the claimed diseases (which encompass any disease or disorder that is characterized or mediated by aberrant HER2 activity, including multiple cancer types that have differing biological mechanisms and clinical characteristics).
In addition, the specification provides no guidance regarding critical aspects of therapeutic use, including appropriate dosing regimens, routes of administration, pharmacokinetic properties, toxicity profiles, or treatment duration. A person of ordinary skill in the art would therefore be required to engage in substantial and undue experimentation to:
identify appropriate disease models, to establish therapeutic efficacy of the claimed compounds in those models,
to determine suitable dosing amounts, dosing frequency, routes of administration of the claimed compounds in a subject with any of the various diseases encompassed by the claims,
and treatment protocols for each of the various diseases in a subject encompassed by the claims.
The breadth of the claims
The claims are broad insofar as the instant claims recite a method of treating any disease or disorder that is characterized or mediated by aberrant HER2 activity which comprises numerous distinct disease entities.
Based off of the above discussion, claim 57 is rejected for failing to comply with the enablement requirement.
Claims 58-63, which are dependent on claim 57, are also rejected for further requiring and/or reciting non-enabling elements as discussed above.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 62 is 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 62 recites the limitation "wherein the cancer”. Claim 62 is dependent on claim 57 which does not mention “a cancer.” Thus, there is insufficient antecedent basis for this limitation in the claim.
Allowable Subject Matter
Claims 51-56, 64, and 65 are allowed.
Conclusion
Claims 51-56, 64, and 65 are allowed. Claims 57-63 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624