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 .
Election/Restrictions
Applicant's election with traverse of Group I (drawn to a compound of Formula (I)), in the reply filed on 04/20/2026 is acknowledged.
Claims 1, 7, 9, 12, 16, 31-34, 36-45, 47-49, 57, 62-63, 67, and 69-71 are pending of which claims 16 and 70-71 (Group II-III) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1, 7, 9, 12, 31-34, 36, 39, 43, 47, 62-63, 67, and 69 have been examined on the merits.
Please note, for clarity of the record, Applicant elected the species, Compound I-54; as shown below and recited in claim 1, 7, 9, 12, 31-34, and 36-45, having the following structure:
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Per MPEP 803.02, the Examiner determined that the elected species is not allowable over the prior art, therefore, the examination of the Markush claim was not extended. Additionally, claims 37-38, 40-42, 44-45, 48-49, and 57, drawn to nonelected species, are withdrawn from further consideration.
Response to argument
Applicant’s election with traverse of Group I in the reply filed on 04/20/2026 is acknowledged. The traversal is on the ground(s) that the restriction requirement of the Group I-III should be reconsidered because a search directed to the elected species would reasonably be expected to lead to prior art relevant to the nonelected species as well. Applicant’s argument is not persuasive, because the restriction requirement is directed to distinct inventions necessitating different search and examination efforts. For example, Groups I and II are directed to different classes of compounds of Formula I and II, which are patentably distinct, requiring different filed of search. Furthermore, Group III is directed to a method of treating cancer, which necessitates an additional search therapeutic use of the compound. Therefore, withdrawal of the restriction requirement would impose a serious burden on the Office by requiring separate searches of distinct group of inventions. The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 112
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.
Claim 1, 7, 9, 12, 31-34, 36, 39, 43, 47, 62-63, 67, and 69 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane), the Federal Circuit noted the importance of an application's disclosure and stated, "the hallmark of written description is disclosure." A disclosure adequately describes an invention when it "reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Id. at 1351. "A 'mere wish or plan' for obtaining the claimed invention is not adequate written description." Centocor Ortho Biotech, Inc. v. Abbott Labs, 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement "varies with the nature and
scope of the invention at issue, and with the scientific and technologic knowledge already in
existence." Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). The Federal Circuit
explained what is required to meet the written description requirement in Ariad Pharm., Inc. v.
Eli Lilly & Co.:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F .3d 1349, 1357-58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including "the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue." Id. at 1359.
A written description of a chemical genus "requires a precise definition, such as by
structure, formula, [or] chemical name" of the claimed subject matter sufficient to distinguish it
from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed.
Cir. 1997). The Federal Circuit reflected on Eli Lil/yin Ariad while explaining how to sufficiently
describe of a genus of compounds:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F .3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
A "representative number of species" must typify the entire claimed genus and account
for variation between the species of the genus.
[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated. Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
Claim 1 recites compounds represented by Formula I, wherein substituents are selected from an extensive set of chemical groups. The size of this genus of claimed compounds may be roughly determined by cumulatively multiplying the number of possibilities, n, for each possible substitution around the rings, specifically at the R1, R2, R3, R5, R6, R7, R8, X1, L,
(#permutations at R1) x (#permutations at R2) x (#permutations at R3) x (#permutations at R4 (#permutations at R5) x (#permutations at R6) x (#permutations at R7) x (#permutations at R8) x (#permutations at R9) x (#permutations at X1) x (#permutations at L) = Total compounds
Taking the R1 to R4, as an example, the number of possible substitutions is not limited, thus, a conservative estimate of the number of possible substitutions would be in the thousands (103) at a minimum. By inserting the optionally substituted groups into the equation, these estimates yield results in the billions (1012) of compounds making up the claimed genus.
By contrast to billions of claimed compounds, the specification provides very few species
of compounds typifying the claimed genus. For example, the specification (page 193-374) depicts about 165 species with very little variation at R1, R2, R3, and R4, i.e., R1 only discloses species in which m is 2, R4 is hydrogen and methyl, and R2 and R3 are absent. The 165 species as presented in the specification and claim 1 are offered to support the genus of billions of compounds account for very little variation as compared to the claimed genus. These 165 supporting species, which lack variation among the substituents, cannot possibly account for the variability found across a genus that encompasses billions of compounds.
Chemistry is generally considered to be unpredictable and/or have unpredictable factors.
See, e.g.,ln re Carleton, 599 F.2d 1021, 202 USPQ 165,170 (CCPA 1979) ("Although there is a
vast amount of knowledge about general relationships in the chemical arts, chemistry is still
largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave."). The pharmaceutical arts, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have
unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) ("In cases
involving unpredictable factors, such as most chemical reactions and physiological activity, the
scope of enablement obviously varies inversely with the degree of unpredictability of the factors
involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 ("chemical reactions frequently are unpredictable").
Considering the unpredictability found in organic synthesis, exchanging even one
substituent for another cannot be considered a foregone conclusion. Accordingly, when a claim
presents a genus with substantial variation as that currently presented by claim 1, the disclosure must adequately reflect such variation with a representative number of species. The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d
1353 (Fed. Cir. 2011).
As is the case here, very few examples do not provide a "representative number of
species" for an unpredictable art such as a chemistry. See, e.g., Ariad, 598 F.3d at 1354-55
(claiming that the inventor has an obligation to disclose examples when the art is unpredictable).
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying
characteristics demonstrating that Applicant was in possession of the entirety of the genus now
claimed, i.e., additional complete or partial structures, other physical and/or chemical properties,
functional characteristics coupled with a known or disclosed correlation between function and
structure, or some combination thereof demonstrating possession of the entirety of the claimed
genus.
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 67 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 67 recites “A compound in Table 3 or 3A, or a pharmaceutically acceptable salt
thereof.” Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609.
(See MPEP 2173.05(s)).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 7, 9, 12, 31-34, 36, 39, 43, 47, 62-63, 67, and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Crew et al., WO 2019/195609 in view of Hansen et al. J. Med. Chem., vol. 61, no. 2, Jan. 2018, pp. 492–503, Chu et al., WO 2021.207172 A1. Please be advised that some of the references are split into Part 1 and Part 2.
Crew (page 1-5; page 1148) discloses bifunctional anticancer compounds with the following features:
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Crew (page 630) discloses the following compound “2-((2S)-1-acryloyl-4-(2-(((2S.4R)-4-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethoxy)ethoxy)-1-methylpyrrolidin-2-yl)meLhoxy)-7-(oaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidio-4-yl)piperazin-2-yl)acetonitrile” wherein R2 and R3 are hydrogen; R1 is a glutarimide ring and m is 2. While the compound has a thalidomide moiety, however, Crew (page 131, emphasis added)
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teaches a broader structural Formula (g) in which W is CH2; and Rn is an C1-C6 alkyl, which corresponds to lenalidomide core, reading on the instant claim. In fact, Crew (page 133 and 138)
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explicitly identifies lenalidomide as an alternative core moiety
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. Therefore, a person of ordinary skilled in the art (POSITA) would recognize and view thalidomide and lenalidomide as predictable alternatives, as both are disclosed as functionally interchangeable options within the glutarimide-phthalimide pharmacophore that mediates binding to cereblon (CRBN). This is further supported by Crew (page 7) where Crew teaches that the pharmacophore core can be, but is not limited to, pomalidomide, lenalidomide and thalidomide and their derivatives.
Crew, however, does not explicitly teach N-phenylurea conjugated to lenalidomide.
Hansen (page 492) discloses lenalidomide-based compounds containing N-phenylurea linker with chloro substituents at different positions on the phenyl ring, including meta-analogue (compound 11). Although, the para-chloro (compound 13) analogue demonstrates a lower EC50 values than the meta-chloro analogue, however, that difference does not make the claimed compound nonobvious. This is because Crew discloses the same scaffold and structure-activity relationship only differ on the placement of chloro-substituents on the phenyl ring. Therefore, a POSITA would have recognized and understood that shifting a chlorine substituent among the available ring position is a routine optimization within a known analogue, as disclosed by Crew.
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Therefore, a POSITA would reasonably expect the meta-chloro isomer to retain the core pharmacophore and offer a different range of potency, and selectivity, to further diversify a compound library and to arrive at the claimed compound. Moreover, it would have been obvious to a POSITA to modify Crew’s teachings by introducing a 3-chloro-N-phenylurea analogs to lenalidomide as taught by Hansen, which teaches that the 3-chloro-N-phenylurea group increases potency of a cancer-related compound. Thus, the improvement of potency of 3-chloro-N-phenylurea to a lenalidomide moiety, would have motivated a POSITA to modify Crew’s teachings in view of Hansen’s disclosure to improve the compound potency and diversify of the compound library.
Regarding X1-L, Crew (page 228-232) discloses the following linker unit, wherein m, n, o, p
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are 0; s is 1; r is 2; and q is 5. It is important to highlight, Crew page (232) teaches a broad linker genus in which the relevant subscript may vary, wherein r, m, s, n, o, p, and q are independently selected from 0 to 20. Thus, the claimed linker falls within a known family of structurally related linkers that is part of the same compound library lenalidomide to the TPL core. For this reason, a POSITA would have understood that varying the subscript to include or remove one or more methylene units would be a predictable modification of Crew’s broader disclosed genus to adjust molecular spacing, flexibility, and target interaction while maintaining the overall molecular structure and biological function of the compound; thus, the claimed linker is an obvious modification of Crew’s teachings.
Regarding TPL, Crew (page 630, emphasis added) discloses the following compound:
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However, regarding the PTL moiety, Crew does not explicitly disclose a β-fluoroacryloyl substituent attached to the piperazine ring, and Crew also does not disclose a chlorine attached to the naphthalene ring. Furthermore, Crew does not explicitly disclose linker attachment at the pyrrolidinyl nitrogen.
Chu (page 662, emphasis added) discloses compound 93 with the structure shown below:
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comprising β-fluoroacryloyl substituent attached to the piperazine ring, and 1-chloro naphthalene. Contrary to Crew’s disclosure, Chu (page 662) teaches the closely related PTL moiety is attached to a linker through the pyrrolidine nitrogen atom, demonstrating that such attachment mode is a recognized alternative within the art. Moreover, although Chu discloses a shorter linker, however, Crew teaches a linker genus that encompasses both the linker cited by Chu and the instant claims. Therefore, a POSITA would have been motivated to modify Crew’s compound in view of Hansen and Chu’s teachings to incorporate the TPL attachment into the bifunctional scaffold, while selecting an appropriate linker length as taught by Crew, in order to diversify the bifunctional compound library and optimize lead compounds in the search for compound possessing certain desirable biological properties. Therefore, it would have been
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obvious with a reasonable expectation of success to a POSITA at the time of filing of the instant application to combine the teachings of Crew, Hansen and Chu of a bifunctional compound to treat cancer and to arrive at the claimed invention, in particular the elected species.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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