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 .
DETAILED ACTION
Status of 18/725,495
Claims 66-85 are currently pending.
Priority
Instant application 18/725,495, filed 6/28/2024, claims priority as follows:
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Support for the instant claims is found in the provisional application.
Information Disclosure Statement
All references from the IDS submitted on 10/29/2024 have been considered unless marked with a strikethrough.
Objection to the Abstract
The abstract of the disclosure is objected to for insufficient length, as it is less than 50 words. The abstract should generally be within the range of 50 to 150 words in length, and chemical abstracts in particular should provide the structure of the compound of a formula thereof in addition to methods of use. See MPEP § 608.01. Appropriate correction is required.
Election/Restriction
Applicant’s election of Group I, claims 66-75, drawn to compounds and compositions of Formula I, without traverse in the reply filed 8/4/2026 is acknowledged. Applicant’s election of compound 102:
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In the same reply, is also acknowledged.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and no prior art was identified. Thus, the search was expanded to compounds of Formula I where D is a ubiquitin ligase binding moiety, L is a linker comprising a fluoro-phenyl substituted with a methoxypropyl group, and S is a SMARCA2 binding moiety, and compounds of Formula II where Q is -C(=O)-, Z is -O-, Y is C3 alkylenyl, also recited as -CH2CH2CH2- in the instant claims, V is
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, where R1 or R2 is fluorine and the other is hydrogen, R3 is hydrogen, R4 is hydrogen, and X is a bond, and W is -CH2-. Stated differently, the search was expanded to compounds that solely differ from the elected species by where the linker is a fluoro-phenyl substituted with a methoxypropyl. See the 103 rejections below. The full scope of the claims has not been searched in accordance with Markush search practice. Claims 66-75 read on the elected species. Claims 76-85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable generic or linking claim.
Claim Interpretation
Claims 72 and 73 recite functional limitations. If the prior art meets the structural limitations of a compound of Formula I recited in claim 66, the claim from which 72 and 73 depend, then the functional limitations would flow from embodiments meeting the structure. The functional limitations do not further limit the structure, and thus are not granted patentable weight.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 72 and 73 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. As stated in the “Claim Interpretation” section above, claims 72 and 73 recite functional limitations and do not further limit the structure of claim 66. Appropriate correction is required.
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.
Claims 67 and 72 are 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 67 recites interpretations of Formula II that are broader than that of instant Formula I of claim 66, the claim from which 67 depends. For example, Formula II of claim 67 allows for the linker to be an ethoxy group attached to a fluoro-phenyl group when Z is -O-, Y is C2 alkylenyl, also recited as -CH2CH2- in the instant claims, V is
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, where R1 or R2 is fluorine and the other is hydrogen, R3 is hydrogen, R4 is hydrogen, and X is a bond, and W is -CH2-, whereas claim 66 does not allow for that linker. Thus, there is a lack of antecedent basis for claim 67. Appropriate correction is required.
Claim 72 recites instances of parentheses. The phrases within the parentheses are indefinite because they are exemplary language and it is not clear if the contents of the parentheses are required, or just examples of what is required. Appropriate correction is required.
Claim Rejections – Improper Markush
Claims 66-75 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
With respect to claim 66, the Markush groupings of Formula I are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons: The Markush groups D, L, and S contain variables that can be independently selected from various ubiquitin ligase binding moieties, fluorophenyl or di-fluorophenyl linkers, and SMARCA2 binding moieties, respectively. The claims and specification do not further define these variables, and thus, the broadest reasonable interpretations of the variables D, L, and S are vast. The compounds of Formula I share no common core. A skilled artisan would recognize the variation in ubiquitin ligase binding moieties, fluorophenyl or di-fluorophenyl linkers, and SMARCA2 binding moieties can lead to variations in biological and chemical properties such as bond angles and binding pose of the substrate in the target. They do not belong to the same recognized physical or chemical class or to the same art-recognized class.
The instant specification discloses compounds that have the property of SMARCA2 and SMARCA4 degradation, in addition to treatment of HCC515 lung cancer in mice. These scope of the compounds tested compared to the instant claims is small; the ubiquitin ligase binding moieties, fluorophenyl or di-fluorophenyl linkers, and SMARCA2 binding moieties are merely a small selection of what is known in the art. For example, the only ubiquitin ligase binding moieties of the compounds of the instant claims is thalidomide. No other data supporting varying ubiquitin ligase binding moieties, fluorophenyl or di-fluorophenyl linkers, and SMARCA2 binding moieties of the common core is disclosed and therefore no structure-function relationship is corroborated. The representative number of examples in this case is small. Futher, in this case, the claims are so expansive that a common utility cannot be expected. Dependent claims 67-75 do not resolve the issue and are therefore also rejected.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 103
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.
Claims 66 and 72-75 are rejected under 35 U.S.C. 103 as being unpatentable over Boehringer Ingelheim International GMBH (WO 2020/078933 A1, cited in the IDS of 10/29/2024, herein after “Boehringer”).
Determining the scope and contents of the prior art
The reference Boehringer teaches proteolysis targeting chimeras as degraders of SMARCA2 and/or SMARCA4 (title, abstract), and specifically teaches bifunctional compounds such as I-15 (page 86):
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Which partially maps to instant Formula I:
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When the moiety highlighted in red is the ubiquitin ligase binding moiety and the moiety highlighted in blue is the SMARCA2 binding moiety. Compound I-15 was placed in DMSO (page 97, lines 2 and 3), indicating a pharmaceutical composition, and was found to be able to degrade SMARCA2 and SMARCA4 in DC50 assays (page 97, Table 1). Compound I-15 differs from a compound of instant Formula I by the linker; it contains a fluoro-phenyl and an ethoxy group, whereas instant Formula I requires the fluoro-phenyl be substituted by a piperazine, piperidine, methoxypropyl, or methoxyethoxy group. However, Boehringer teaches additional compounds able to degrade SMARCA2 and SMARCA4 such as compound I-14 (page 83):
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Which contains a methoxypropyl group, a three carbon chain mapping to the third compound in claim 70, in the linker instead of the two carbon chain in Compound I-15. Further, with respect to claim 75, Boehringer teaches that the SMARCA degraders can be combined with additional pharmacologically active substances, including, but not limited to, hormone analogues or antihormones, aromatase inhibitors, and growth factor inhibitors (page 19, lines 21-32).
Ascertaining the differences between the prior art and the claims at issue
The reference Boehringer fails to teach an anticipatory species of instant Formula I.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of SMARCA2 degrading chimeric molecules. An artisan possesses the technical knowledge necessary to make adjustments to the chimeric molecules to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said SMARCA2 degrading chimeric molecules and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (B), it would have been prima facie obvious to one of ordinary skill in the art to substitute the two carbon chain of Compound I-15 with the three carbon chain of Compound I-14 because both compounds are known to be able to degrade SMARCA2, and structurally similar compounds are expected to have similar properties. Thus, substituting a two carbon chain with a three carbon chain to arrive at a compound of an expanded species would be expected to have similar properties. A skilled artisan would have been motivated before the effective filing date to make such a substitution to identify additional compounds with SMARCA2 degradation activity, and ultimately treat diseases and disorders associated with SMARCA2 degradation in view of the teaching of Boehringer.
Claims 66-75 are rejected under 35 U.S.C. 103 as being unpatentable over Boehringer Ingelheim International GMBH (WO 2020/078933 A1, cited in the IDS of 10/29/2024, herein after “Boehringer”) in further view of Kymera Therapeutics, Inc. (WO 2020/251971 A1, cited in the IDS of 10/29/2024, herein after “Kymera”).
Determining the scope and contents of the prior art
Boehringer teaches as disclosed above, and at least those teachings are incorporated herein. Furthermore, Compound I-15 of Boehringer partially maps to a compound of instant Formula II:
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When Z is -O-, Y is C2 alkylenyl, also recited as -CH2CH2- in the instant claims, V is
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, where R1 or R2 is fluorine and the other is hydrogen, R3 is hydrogen, R4 is hydrogen, and X is a bond, and W is -CH2-. Compound I-14 maps in almost the same way, and only differs in the variable Y, which is C3 alkylenyl, also recited as -CH2CH2CH2-in the instant claims. Compounds I-15 and I-14 of Boehringer differ from a compound of instant Formula II by the ubiquitin ligase binding moiety because instant formula II recites thalidomide as the moiety, whereas Boehringer teaches a moiety able to bind VHL.
However, this deficiency is taught by Kymera. The reference Kymera teaches SMARCA2 degraders (abstract), and specifically teaches compounds such as I-36 (page 252):
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Which teaches the ubiquitin ligase moiety of Formula II where Q is -C(=O)- with the same ether connection and position of attachment to the linker moiety as the expanded species.
Ascertaining the differences between the prior art and the claims at issue
The reference Boehringer fails to teach an anticipatory species of instant Formula II because Boehringer fails to teach thalidomide as the ubiquitin ligase binding moiety.
The reference Kymera fails to teach an anticipatory species of instant Formula II.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of SMARCA2 degrading chimeric molecules. An artisan possesses the technical knowledge necessary to make adjustments to the chimeric molecules to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said SMARCA2 degrading chimeric molecules and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (B), it would have been prima facie obvious to one of ordinary skill in the art to substitute the ubiquitin ligase binding moiety of Boehringer with the ubiquitin ligase binding moiety of Kymera because both are known to be successful ubiquitin ligase binding moieties in SMARCA2 degradation. PROTACs are known in the art to be modular, as evidenced by Formula I recited in instant claim 1, and therefore a skilled artisan would be motivated before the effective filing date to make such a substitution to identify additional compounds able to degrade SMARCA2. Further, a skilled artisan would reasonably expect success of the substitution in light of the teachings of Boehringer and Kymera.
Conclusion
Claims 66-75 are rejected. Claims 76-85 are currently withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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