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 .
Priority
The instant application, filed 10/30/2023, is a CON of provisional U.S. application number 16/809,336, filed 03/04/2020, a CON of PCT/EP2018/073578, filed 09/03/2018, and claims foreign priority to EP17189231.8, filed 09/04/2017. Receipt is acknowledged of certified copies of papers required by 37 CFR § 1.55.
Amendments and Claim Status
The amendment filed on 09/02/2025 is acknowledged and entered.
Claims 1, 2, 7, and 8-15 are amended;
Claims 1-15 are pending and are under prosecution.
Response to arguments
Applicant’s arguments filed 09/02/2025 with respect to the statement of foreign priority, as well as the rejections under 35 U.S.C. §§ 112(a) and 102 (a) (1/2) have been fully considered.
With respect to the Foreign Priority statement, the arguments submitted by Applicant as well as the inclusion of the foreign priority document in the attachments filed 09/02/2025 is sufficient to grant priority to the foreign document EP17189231.8, filed 09/04/2017.
With respect to the rejection under U.S.C. § 112(a), the removal of “for the treatment of cancer comprising” and the addition of “to alter the substrate specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human patient, wherein the method comprises “ to claim 1 is insufficient to overcome the previously made 112a rejections. Furthermore, the amendment has necessitated both an amendment to the existing 112a rejections as well as a new rejections on the grounds of 35 U.S.C. § 112(a) and (b), included herein.
With respect to the rejections of claims 1-3, 5, and 6 under 35 U.S.C. § 102 (a) (1/2) as being anticipated by Huang et al. (Chinese Journal of Pharmaceuticals (1993), 24(10), 437-441, published 1993), hereinafter Huang and Burnette et al. (WO 2017161119 A1, published September 21, 2017), hereinafter Burnette, the claim amendments are sufficient to overcome the rejections.
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.
Claims 1-15 are rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ) first paragraph, because the specification, while being enabling for the synthesis of the compounds of Formula (I) (page 51-89) as well as their ability to bind hCereblon_DDB1 (page 34), does not reasonably provide enablement for a method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising the administration of a compound of Formula (I).
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: claims 1-15 of the instant application are drawn to a method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising the administration of a compound of Formula (I). The claims encompass altering the activity of any Cereblon (CRBN) E3 ubiquitin ligase complex, according to the claim interpretation applied, above.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the claimed compounds can be used to alter the activity of any Cereblon (CRBN) E3 ubiquitin ligase complex. Thus the cited claims are deemed very broad because they read on changing any and all of the target proteins which the E3 ligase recognizes and ubiquitinates.
State of the Prior Art: The state of the prior art does not currently support that any compound capable of binding to Cereblon (CRBN) E3 ubiquitin ligase will alter complex specificity. By contrast, the current state-of-the-art teaches that alteration of E3 ligase substrate specificity is achieved only under narrow conditions involving a defined PROTAC architecture and mechanistically verified CRBN-mediated ubiquitination. In recent investigations of E3-ligase substrate specificity alteration, Li et al (Chem Biol, Vol 22, page 755-763, published June 18, 2015), hereinafter Li describes the first successful use of a heterobifunctional small molecule to greater (“ARV-825”) to recruit the promo domain protein (BRD4) to the E3 ubiquitin ligase Cereblon (CRBN), thereby inducing rapid and efficient proteosomal degradation of BRD4 (Abstract). Specifically, Lu constructed ARV-825 by covalently linking a BRD4-binding moiety to a Cereblon-binding moiety (pomalidomide) via a flexible polyethylene glycol linker (Figure 2A). The compound simultaneously engages BRD4 and CRBN to form a ternary complex that promotes ubiquitination of BRD4, resulting in its destruction to the proteasome (page 756). The linker architecture and conformational flexibility is thought to critically affect degradation potency and selectivity amongst BRD substrates (page 761). Accordingly, Lu establishes that chemical hijacking of an E3 ligase to a non-native substrate is possible only by using a bifunctional molecule simultaneously binds both the ligase and target protein.
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses altering the specificity of any and all Cereblon (CRBN) E3 ubiquitin ligase complexes by administering a compound of Formula (I), and the skilled artisan would view that this is highly unpredictable.
Guidance of the Specification/Working Examples: Applicant has only provided examples of capillary-based immunoassays to measure endogenous BRD4 levels (page 33 of the instant specification). While these observations suggest a biological effect on BRD4 abundance, the specification does not teach or enable the mechanistic alteration of E3 ligase substrate specificity, as recited in the instant claims. While this data demonstrates that the compound exposure correlates with decreased BRD4 abundance, the experiments merely measure overall protein levels, and ligand binding to Cereblon. They do not establish that the compounds alter the substrate recognition properties of the complex. There is no disclosure of detection of ternary complex formation, no demonstration of proteosome dependence, no ubiquitination assays, no comparative analyses, and no structural biochemical data showing that the E3 ligase acquires new substrate recognition capacity upon compound binding. The disclosure supports, at most, a correlation between compound treatment and changes in BRD4 detection, which at present, cannot be inextricably linked to specificity alteration in the E3 ligase. Thus, the specification fails to provide sufficient evidence in support of the broad method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising the administration of a compound of Formula (I).
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that any cancer could be treated by the administration of the compounds claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
The instant specification lacks structural, mechanistic, and experimental details and therefore does not enable a person of ordinary skill in the art to practice the claimed method without undue experimentation. Consequently, the result presented in the specification are insufficient to establish or enable alteration of E3 ligase specificity. A method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising the administration of a compound of Formula (I) is not enabled by the instant specification.
Claims 1-15 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 claims contain 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.
Claims 1-15 of the instant application claim a method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising administering a compound of Formula (I).
35 U.S.C. § 112 (a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc); Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111,1114 (Fed. Cir. 1991); see also Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004) (discussing the history and purpose of the written description requirement); In re Curtis, 354 F.3d 1347, 1357, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) ("conclusive evidence of a claim’s enablement is not equally conclusive of that claim’s satisfactory written description"). The written description requirement has several policy objectives. "[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed." In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert, denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Bees., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); EliLilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm.,927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991). An application specification may show actual reduction to practice by describing testing of the claimed invention.
In the present case, the important factors leading to a conclusion of inadequate written description are the absence of any working example of the invention as claimed and the lack of predictability in the art.
In the instant specification, there is no disclosure of a method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject comprising the administration of a compound of Formula (I). In the instant specification, it is stated that “The present invention provides compounds which bind to the ubiquitously expressed E3 ligase protein celebron (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins. The compounds of present invention can further be used as part of bifunctional compounds that comprise the compounds of present invention as E3 Ubiquitin Ligase moiety that is linked to a moiety that binds to a target protein where the target protein is proximate to the ubiquitin ligase to effect degradation of said protein” (page 2). The specification further states, “the terms "treating", "contacting" and "reacting" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product” (page 6).
It is also stated in the instant specification that “In order to measure BRD4 protein abundance in a mammalian cell system at medium throughput, a dual fluorescent reporter system was developed” (page 32). Finally, the instant specification teaches “The biological activity of selected compounds (cut-off > 20% reduction in BRD4-eGFP levels) was confirmed in an additional assay (page 33) which simply allowed for the quantification of endogenous BRD4 levels in a chemical assay, as stated earlier.
There are no working examples in the instant specification for a method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex in a human subject and thus the instant specification does not provide any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application.
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F. 3d 1565, 1572, 41 USPQ2d 1961, 1966(1997); In re Gosteli, 872 F.2d 1008, 1012,10 USPQ2d 1614, 1618 (Fed Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.") Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For example, disclosure of only a method of making the invention and the function may not be sufficient to support a product claim other than a product-by-process claim. See, e.g., Fiers v. Revel, 984 F.2d at 1169, 25 USPQ2d at 1605; Amgen, 927 F.2d at 1206, 18 USPQ2d at 1021.
Thus, since Applicant has not described in adequate detail the method of altering the specificity of the Cereblon (CRBN) E3 ubiquitin ligase complex and furthermore has not provided any evidence that such alteration exists, an ordinary skilled artisan could not completely envisage Applicants’ invention. Moreover, it is clear that the written description requirement has not been met since Applicant has not provided any evidence that Applicant was in possession of the claimed invention prior to the effective filing of the instant application. Thus, claims 1-15 of the instant application are not supported by the instant specification and thus a rejection under 35 USC § 112 (a) for failing to comply with the written description requirement is proper.
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 8 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 8 recites the limitation "benzothiophenyl" in the list of R1 substituents. There is insufficient antecedent basis for this limitation in the claim, as this is not listed as one of the possible substituents of R1 included in the newly amended claim 1, on which claim 8 depends.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623