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 .
This is the first action on the merits.
Election/Restrictions
Applicant's election without traverse of Group (I) in the reply filed on April 28, 2026 is acknowledged. Group (I), drawn to compounds of formula (I), embraced by claims 1, 3, 5, 6, 12, 14, 24, 31-33, 36, 38, 41-43 and 45 was elected by Applicant. Applicant has not pointed to any errors in the Examiner’s analysis of the different inventions. The requirement is still deemed proper and is therefore made FINAL.
Applicant elected the following species:
PNG
media_image1.png
427
153
media_image1.png
Greyscale
and indicated claims 1, 3, 5, 6, 24, 31-33, 36, 38 and 41-43 read on said species.
Claims 1, 3, 5, 6, 12, 14, 24, 31-33, 36, 38, 41-43, 45, 48, 102-104, 106, 111, 114, 126, 138, 140, 145-148, 167 and 174 are pending and claims 1, 3, 5, 6, 24, 31-33, 36, 38 and 41-43 are under examination. Claims 12, 14 and 45 are withdrawn based on the species election and claims 48, 102-104, 106, 111, 114, 126, 138, 140, 145-148, 167 and 174 are withdrawn based on the lack of unity
Specification
The disclosure is objected to because of the following informalities: several of the formulas in the specification are too blurry, e.g. see page 50, compounds 245, 248, etc. Please review all formulas and address accordingly. Appropriate correction is required.
Claim Objections
Claim 43 is objected to because of the following informalities: several of the formulas in the specification are too blurry, e.g. see page 50, compounds 244, 245, 247, 248, etc. Please review all formulas and address accordingly. Appropriate correction is required.
Claim Rejections
Claims 1, 3, 5, 6, 24, 31-33, 36, 38 and 41-43 are rejected as each directed to an improper Markush group. These Markush claims are rejected under the judicially approved ‘‘improper Markush grouping’’ doctrine when the claim contains an improper grouping of alternatively useable species. In re Harnisch, 206 USPQ 300 (CCPA 1980). A Markush claim contains an ‘‘improper Markush grouping’’ if: (1) the species of the Markush group do not share a ‘‘single structural similarity,’’ or (2) the species do not share a common use. The species of the present claims do not share a ‘‘single structural similarity. Therefore, a rejection on the basis that the claims contain an ‘‘improper Markush grouping’’ is appropriate. The rejection of the claims will be maintained on the basis that the claims contain an ‘‘improper Markush grouping’’ until the claims are amended to include only species that share a single structural similarity and a common use, or the applicant presents a sufficient showing that the species in fact share a single structural similarity and a common use.
Under principles of compact prosecution, the applicant elected a single disclosed species for search and examination (i.e., an election of species). The prior art search did not find the elected species in the prior art, and the search has been extended to those additional species that fall within the scope of a permissible Markush claim. In other words, the search has been extended to the species that share a single structural similarity and a common use. Proper Markush claims will be examined for patentability over the prior art with respect to the elected species or group of indistinct species, as well as the species that share a single structural similarity and a common use with the elected species or group of indistinct species (i.e., the species that would fall within the scope of a proper Markush claim). Federal Register, Vol. 76, No. 27, 02-09-2011, page 7166.
Claims 1, 3, 5, 6, 24, 31-33, 36, 38 and 41-43, directed to the nonelected species, are withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
To overcome the rejection, the claims may be amended to the elected Markush group, wherein the MCL-1 ligand moiety is drawn to formula (A), which is not part of another ring system, Z2= carbon,
PNG
media_image2.png
31
41
media_image2.png
Greyscale
is a double bond and the linker is through the R8 variable.
Claim Rejections - 35 USC § 112
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 4 and 24 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 pre-AIA the applicant regards as the invention.
In claim 4, the phrase, “naphthyl is optionally substituted with -O- or -S-“ is vague. The oxygen and sulfur are valent deficient as a substituent on a naphthyl ring, see page 4, lines 4-5 and page 5, lines 2-3.
To overcome the rejection, the phrase may be removed.
Regarding claim 24, the term “piperazine N-oxide” lacks antecedent basis.
To overcome the rejection, the term may be removed
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1, 3, 5, 6, 24, 31-33, 36 and 38 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification does not provide specific description for “isomers” and just a mere recitation of “isomers” is not sufficient to comply with the written description requirement. As noted above, here are many different kinds of isomers, e.g. regioisomers, constitutional isomers, stereoisomers, etc. Constitutional isomers are isomers with different connectivity that have the same molecular formula. For example, n-propanol and methyl ethyl ether have the same molecular formula, C3H8O but are entirely different molecules. Therefore, said claims lack written description.
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 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.
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.
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:
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.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1, 3, 5, 6, 24, 31-33, 36, 38 and 41-43 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Papatzimas et al. (Journal of Medicinal Chemistry, (2019), 62, 5522-5540) in view of Wang et al. (US 20140051683).
The present application claims compounds of formula (I), [MCL-1 ligase moiety-linker-ligase ligand moiety], wherein the ligase moiety (CRBN or degrader or lenalidomide) is
PNG
media_image3.png
312
304
media_image3.png
Greyscale
, wherein M is oxygen and L’ is hydrogen; the MCL-1 ligand moiety is
PNG
media_image4.png
217
214
media_image4.png
Greyscale
, wherein Z2 is carbon,
PNG
media_image2.png
31
41
media_image2.png
Greyscale
is a double bond, R8 is linker, R9 is COOH, R10 is propyl-O-7-fluoro-naphthyl, R11 is chloro, and R12 is 1,2,4-trimethyl-3-pyrazolyl; and the linker is ethyl-1,4-piperazinyl-C(O)-methyl-, see the elected species below:
PNG
media_image1.png
427
153
media_image1.png
Greyscale
.
Papatizimas et al. teaches “An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a critical prosurvival factor in cancers such as multiple myeloma where MCL1 levels directly correlate to disease progression. Current strategies for halting the antiapoptotic properties of MCL1 revolve around inhibiting its sequestration of proapoptotic factors. Existing inhibitors disrupt endogenous regulatory proteins; however, this strategy actually leads to an increase of MCL1 protein levels. Here, we show the development of hetero-bifunctional small molecules capable of selectively targeting MCL1 using a proteolysis targeting chimera (PROTAC) methodology leading to successful degradation,” see the abstract.
The reference teaches a compound similar to the elected species as shown below with the linker being part of both the MCL-1 ligand moiety and the ligase ligand moiety:
PNG
media_image5.png
189
314
media_image5.png
Greyscale
PNG
media_image6.png
211
390
media_image6.png
Greyscale
.
The only differences between the claimed elected species and the cited PROTAC compound above are 1) the MCL-1 portion of the PROTAC molecule; and 2) the ligase ligand moiety, thalidomide versus Applicant’s lenalidomide.
The same reference teaches “Notably, all of thalidomide, lenalidomide, and pomalidomide recruit CRBN and are existing clinical therapies for MM,” see page 5523, right-hand column, second full paragraph. Thus, thalidomide and lenalidomide are taught as alternatively useable and therefore, equivalent.
The lenalidomide is connected at a difference position than the elected species. However, these are positional isomers. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Papatizimas does not teach the MCL-1 ligand moiety.
Wang et al. teach the following species as an inhibitor of the anti-apoptotic MCL-1 protein, see page 10, paragraph [0417]:
PNG
media_image7.png
363
905
media_image7.png
Greyscale
.
The only differences between the claimed MCL-1 portion of the PROTAC molecule are 1) the instant R11, H versus Applicant’s chloro atom; and 2) H versus Applicant’s F substituted on the naphthyl ring of the R10.
The reference on page 1, paragraphs [0004] and [0029] teaches H and Cl are alternatively useable at R11. Thus, it would be obvious to substituted H for Cl since the reference teaches the equivalency of said atoms.
The reference on pages 1 and 2, paragraphs [0004], [0018], [0023]-[0025], and [0038] teaches H and F at this position of the naphthyl ring are alternatively useable. Thus, it would be obvious to substituted H for F since the reference teaches the equivalency of said atoms.
Therefore, it would be obvious to substitute the MCL-1 ligase moiety as taught by Wang et al. into the PROTAC that is taught by Papatizimas et al. to obtain the presently claimed elected species.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 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, Jeffrey Murray can be reached on 571-272-9023. 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.
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
Prosecution Insights