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
1. This application is a 371 of PCT/EP2021/069897 07/15/2021; FOREIGN APPLICATIONS: EP 20186249.7 07/16/2020.
2. Claims 1-15 are pending.
Response to Restriction Election
3. Applicant’s election of the species,
PNG
media_image1.png
134
148
media_image1.png
Greyscale
,
in the reply filed on December 15, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)). According to applicants’ representative claims 1-3, 5-6, 8, 11-15 read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claims 4, 7, 9-10, which does not read on the elected species are withdrawn.
Claim Rejections - 35 USC § 112
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.
3. Claims 14-15 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. The limitations “for use….” are not limiting because the claim describes a structurally complete invention and the functional language only refers to properties of that structure. A claim may recite features of a compounds utility, but the patentability of the compound depends upon the claimed structure, not the use or purpose of that structure. To limit a compound the functional language must result in a structural difference in the claimed compound. This would require a chemical or nuclear change to atoms of the claimed compound. None of the recited language alters the number of protons in the nucleus of any atom nor adds or removes any atoms from the structure, and the structure is unchanged. Since the language does not structurally limit or affect the compound structure and only states an intended use or purpose of the invention, the language is not limiting. See also MPEP § 2112 - MPEP § 2112.02. Functional language is not limiting where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a functional purpose or intended implementation of the invention. This is grounded in the statutory distinction, between a physical product and activities that constitute a process (which may include a new “use” of a known invention). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
4. Claims 1-2, 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Piu WO 2008033894 A2 in view of Fleming “Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.” J. Med. Chem. 2010, 53, 7902–7917. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
Determining the scope and contents of the prior art:
Piu teaches the des-cyano compounds of the instant claims on page 12 useful as estrogen receptor ligands:
PNG
media_image2.png
151
179
media_image2.png
Greyscale
PNG
media_image3.png
137
182
media_image3.png
Greyscale
PNG
media_image4.png
138
178
media_image4.png
Greyscale
Page 17 defines a genus encompassing those species:
PNG
media_image5.png
181
230
media_image5.png
Greyscale
PNG
media_image6.png
76
598
media_image6.png
Greyscale
The substituents described for R6 include -CN:
PNG
media_image7.png
161
575
media_image7.png
Greyscale
These would be claimed compounds where instant R1/R2 are H, m is 1, R3/R4 are aryl (phenyl) which are substituted with -OC1-6alkyl (R6) or R11 (choice (7) where p is 0, and R14 is alkyl).
According to Fleming page 7902 col. 1, “Over 30 nitrile-containing pharmaceuticals are prescribed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. Trends identifying the roles of the nitrile in medical agents have emerged as the number of nitrile-containing pharmaceuticals has increased.” Fleming on page 7909 col 2 last parargraph dicsusses the choice of nitrile as a preferred substituent in drugs, “7. The nitrile group improvesADME178-toxicology profiles. Computational properties and empirical rules such as Lipinski’s rules179 are routinely employed to guide structure-based drug design. While a potent molecule is essential for drug discovery, ultimately ADME-Tox properties decide which molecule is advanced into clinical trials. During optimization, leads tend to increase in size and lipophilicity180 which can be offset by introducing the sterically insignificant nitrile group. Replacing a hydrogen with a nitrile can roughly lower cLogP181 by half an order of magnitude and nearly an order of magnitude reduction for logD.182 A more dramatic decrease in lipophilicity by over a full order of magnitude for cLogP/logD often occurs when replacing a halogen or methyl group by a nitrile.”
Ascertaining the differences between the prior art and the claims at issue.
The compounds of Piu above have an H atom in the cyclohexenone, while the claimed compounds have a nitrile (-CN) in this position.
Finding of prima facie obviousness
Rational and Motivation
(MPEP 2142-2143)
It was prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to prepare cyano analogs of those of the Piu to produce the claimed compounds because he or she would expect the compounds to have similar properties and even improved properties. This substituent was explicitly listed as an option for R6 by Piu in the generic description. The replacement of H with CN, was known at the time the invention was made to lead to improved properties in drug compounds as shown by Fleming. The CN analogs have sufficient similarity in size and shape to the non-cyano analogs to fit the active site of the target protein, so they would be expected to have similar inherent biological activity and improved half-life based upon reduced metabolism and increased lipophilicity which would improve bioavailability. This is the strongest rationale as set forth in the MPEP 2144, “II. THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”
5. Claims 1-3, 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bartholomeus WO 2019122265 A1 (cited on the IDS) in view of Silverman, R.B. The Organic Chemistry of Drug Design and Drug Action 1992, Academic: New York, pg 19. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
Determining the scope and contents of the prior art
Bartholomeus WO ‘265 including but not limited to those on page 64, 67, 74, 76, 82, 95 which have the same utility as KEAP1 inhibitor:
PNG
media_image8.png
169
145
media_image8.png
Greyscale
PNG
media_image9.png
144
143
media_image9.png
Greyscale
PNG
media_image10.png
131
142
media_image10.png
Greyscale
PNG
media_image11.png
164
113
media_image11.png
Greyscale
PNG
media_image12.png
142
133
media_image12.png
Greyscale
PNG
media_image13.png
158
134
media_image13.png
Greyscale
PNG
media_image14.png
135
147
media_image14.png
Greyscale
PNG
media_image15.png
137
117
media_image15.png
Greyscale
Other examples with similar structure on are given in the Table 2 on page 113ff.
PNG
media_image16.png
129
198
media_image16.png
Greyscale
A compound on page 122 has R1/R2 forming a cyclopropane as do thos in Table 4 on pages 126ff:
PNG
media_image17.png
190
139
media_image17.png
Greyscale
others have a cyclopentane
PNG
media_image18.png
201
203
media_image18.png
Greyscale
Many additional examples appear in Table 8 pages 155 ff.
A genus is formulated on page 6 which is similar to that claimed:
PNG
media_image19.png
256
682
media_image19.png
Greyscale
PNG
media_image20.png
90
628
media_image20.png
Greyscale
These would be claimed compounds where instant R1/R2 are H or alkyl or fomr various spirocycles, m is 1, R3 are aryl (phenyl), and various heteroaromatics which are substituted with halogen, alkyl (R6) or other choices.
Silverman teaches that “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.” He goes on to state “Erlenmeyer’s 1948 definition of “classical isosteres” as “atoms, ions, or molecules in which the peripheral layers of electrons can be considered to be identical”. Table 2.2 lists several of these classical isosteres under heading 1a, establishing that –OH and –NH2 are classical bioisosteres as well as the bivalent -O- and -NH- groups.
Ascertaining the differences between the prior art and the claims at issue.
The compounds of Bartholomeus above have an hydroxy group (-OH) or alkoxy group while the instant claims are drawn to -NH2 or secondary amino isosteres. At least where the R3 substituent is NR7R8 (R7/R8 is H or alkyl), the instant claims are drawn to the amino isosteres of the prior art compounds.
Resolving the level of ordinary skill in the pertinent art
One of ordinary skill would be motivated to make the compounds of the invention because he or she would expect the compounds to have similar properties. Making a conservative substitution like an -OH to amino isostere, rather than complete removal of the polar character, would be expected to maintain activity. Silverman teaches that “Bioisosteres are substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties.” He goes on to state “Erlenmeyer’s 1948 definition of “classical isosteres” as “atoms, ions, or molecules in which the peripheral layers of electrons can be considered to be identical”. Table 2.2 lists several of these classical isosteres under heading 1a, establishing that –OH and –NH2 as well as the bivalent -O- and -NH- groups are classical bioisosteres. The experienced medicinal chemist would be motivated to prepare these bioisosteres based on the expectation that such bioisosteres would have similar properties and upon the routine nature of such experimentation in the art of medicinal chemistry. Based upon the teachings of Silverman making the bioisosteric amino variant of the -OH or ether compounds of Bartholomeus would be expected to give compounds with similar KEAP1 activity, which is what has been shown.
Objections
6. Claim 5-6, 8, 11-12 is objected to for depending from a rejected base claim, but would be allowable in independent format with all the requisite limitations of the base claim and any intervening claim.
Conclusion
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 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 an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/DAVID K O'DELL/ Primary Examiner, Art Unit 1621