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 17/642,292
Claims 40-50 are currently pending.
Priority
Instant application 17/642,292, filed 3/11/2022, claims priority as follows:
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Receipt of the certified copy of the foreign application is acknowledged.
Information Disclosure Statement
All references from the IDS’s filed 2/14/2023, 9/1/2023, 3/15/2024, 5/7/2024, 5/17/2024, 12/9/2024, and 9/12/2025 have been considered unless marked with a strikethrough. The Examiner notes the references struck through on the IDS filed 9/12/2025 were not submitted.
Response to Arguments/Amendments
The amendment filed 9/12/2025 has been entered. Applicant has cancelled all claims, claims 1, 3-14, 19-20, 24, 30-31, and 35, and added claims 40-50. New claims 40-50 are not considered new matter.
In the Non-Final dated 3/12/2025, the abstract was objected to for improper content. Applicant did not address this objection in the response dated 9/12/2025 and thus, the objection is maintained.
Claim 9 was objected to in the Non-Final dated 3/12/2025 for improper valency of a nitrogen in a substituent. In response, Applicant has cancelled claim 9 to overcome the objection. The objection is withdrawn.
In the Non-Final dated 3/12/2025, claims 1 and 9-11 were rejected under 35 U.S.C. 112(b). In response, Applicant has cancelled all claims to overcome and withdraw the rejection.
Claims 1, 3-4, 6-11, and 13-14 were rejected under 35 U.S.C. 112(a) in the Non-Final dated 3/12/2025. Upon cancellation of all claims, the rejections have been overcome and withdrawn.
In the Non-Final dated 3/12/2025, claims 1, 3-4, 6-11, and 13-14 were rejected on the basis that they contain an improper Markush grouping of alternatives. Similar to above, after Applicants’ cancellation of all claims, the rejection has been overcome and withdrawn.
Claims 1, 3-4, 6-11, and 13-14 were rejected under 35 U.S.C. 103 in the Non-Final dated 3/12/2025. Upon cancellation of all claims, the rejection has been overcome and withdrawn.
However, newly added claims 40-50 contain rejections disclosed herein.
Election/Restriction
Applicant’s election of Group I (claims 1 and 3-14), drawn to compounds and compositions able to bind to cereblon E3 ligase, further defined by Formula (I), without traverse in the reply filed 2/18/2025 is acknowledged. Further, Applicant’s election of 1-(benzofuran-3-yl)dihydropyrimidine-2,4(1 H,3H)-dione:
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without traverse in the reply filed 2/18/2025 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 applicable prior art was identified in the Non-Final dated 3/12/2025. The Examiner then expanded her search to compounds of Formula (I):
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when
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is a single bond, Rd1 is H, Rd2 is H, and Rd3 is
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91
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.
:
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.
and identified prior art. In response, Applicant cancelled claims 1, 3-14, 19-20, 24, 30-31, and 35, to overcome and withdraw these rejections, and added claims 40-50. Furthermore, the addition of claims 40-50 with a narrower genus reinstates unity of invention, as the art provided in the Requirement for Restriction/Election is no longer viable. Thus, the Requirement for Restriction/Election dated 12/17/2024 has been withdrawn. The full scope of instant Formula (I) in the claim set dated 9/12/2025 was searched, and no prior art was identified.
MAINTAINED OBJECTIONS
Objection to Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. In the instant case, no general nature of the compounds nor an exemplification of species is given. See MPEP § 608.01(b). Appropriate correction is required.
NEW OBJECTIONS/REJECTIONS NECESSITATED BY AMENDMENT
Claim Objections
Claims 41 and 42 are objected to as they recite, “thereof,,”, but should read, “thereof,”. Appropriate correction is required.
Claim 46 is objected to as it recites, “1-(6-ethynylbenzofuran-3-yl)dihydropyrimidine-2,4( 1H, 3H)-dione” twice. Appropriate correction is required.
Claim Rejections
Claim Rejections - 35 USC § 112(a)
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 49 and 50 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The instant specification, while being enabled for IKZF1, GSPT1, and SALL4 protein reduction, does not reasonably provide enablement for treating or preventing all other disorders, diseases, or conditions mediated by cereblon or IKZF1, GSPT1, or SALL4. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples, and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the Invention
The invention is drawn to compounds of Formula (I), recited in claims 40-46 and found on pages 128-130 of the specification. The compounds are disclosed as molecular glues that bind to cereblon and target a protein, in this case IKZF1, GSPT1, or SALL4.
Breadth of the Claims
The claims are broadly directed to the use of compounds of Formula (I) for the treatment or prevention of all disorders, diseases, or conditions mediated by cereblon, IKZF1, GSPT1, or SALL4. The genus of disorders, diseases, or conditions mediated by cereblon disclosed in the instant application is stated on page 31, lines 8-13:
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Whereas the genus of disorders, diseases, or conditions mediated by the target protein, in this case IKZF1, GSPT1, or SALL4, is defined in the specification on page 306, lines 24-27:
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As defined on page 29, starting on line 4, of the instant specification, the “subject” is a mammal, e.g. a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or nonhuman primate, such as a monkey, chimpanzee, baboon, or rhesus.
Level of Ordinary Skill in the Art
The artisans using Applicant’s method would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical arts, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
For example, different types of disorders, diseases, or conditions in a subject mediated by cereblon, IKZF1, GSPT1, or SALL4 affect different organs and have different and have different methods of growth and/or harm to the body, and different vulnerabilities. The skill thus depends on the disorders, diseases, or conditions in a subject mediated by cereblon, IKZF1, GSPT1, or SALL4. There are some diseases where the skill level is high and there are multiple successful therapeutic treatments. The mechanism of action in these situations, however, is not necessarily the same as is alleged for these compounds.
State of the Prior Art and Predictability in the Art
At the time of filing, there were multiple compounds in development as molecular glues to target proteins IKZF1, GSPT1, or SALL4, and a variety of scaffolds are present in literature that “glue” together CRBN and said proteins (Sasso, J. M. et. al. Biochemistry, 2023, 62, 601-623). However, none have been shown to have a broad spectrum of treatment and prevention of all diseases, disorders, or conditions mediated by CRBN, IKZF1, GSPT1, or SALL4. Further, there are different types of treatments available for diseases, disorders, or conditions mediated by CRBN, IKZF1, GSPT1, or SALL4, such as cancer, including surgery, chemotherapy, hormonal therapy, biological therapy, and radiation. Not every treatment option is effective for every patient, and for some patients, combinations of the above treatment options are necessary to manage their symptoms. Therefore, the ability to treat diseases, disorders, or conditions mediated by CRBN, IKZF1, GSPT1, or SALL4 is unpredictable, much less the ability to anticipate which patients are at risk for said diseases, disorders, and conditions.
For example, Sasso was identified during the search, and reviews targeted protein degradation, particularly molecular glues (abstract). The Examiner acknowledges that the publication date of Sasso is after the that of the instant application's priority date; however, Sasso is relied upon to demonstrate the scope of the diseases, disorder, and conditions mediated by CRBN, IKZF1, GSPT1, or SALL4 and the limited reach of molecular glues even after the effective filing date. Specifically, Sasso discloses discovered molecular glues in the clinical development pipeline and diseases they treat, which includes cancers and systemic lupus erythematosus (Figure 11). Additionally, Sasso discloses that the degradation of IKZF1 can lead to antiproliferative activity in cancer and treat two immune disorders (Table 3) and degraders of GSPT1 can treat cancers (Table 6), but does not disclose the treatment of the broad scope of diseases, disorders, and conditions of the instant disclosure nor the prevention of said diseases, disorders, and conditions. Further, Sasso does not disclose disease, disorders, or conditions treated or prevented by degradation of SALL4 (page 613). No other evidence of treating or preventing the full scope of diseases, disorders, or conditions mediated by CRBN, IKZF1, GSPT1, or SALL4 was provided.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Furthermore, there is no evidence of record, which would enable the skilled artisan in the identification of the people who have the potential of becoming afflicted with the numerous disorders, diseases, or conditions claimed herein. That a single compound or class of compounds can be used to treat or prevent all disorders, diseases, or conditions mediated by cereblon, IKZF1, GSPT1, or SALL4 in a subject embraced by the claims is an incredible finding for which Applicant has not provided supporting evidence. Applicant has not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use for treating any or all the diseases, disorders, or conditions by administering the instant claimed compounds.
Amount of Direction Provided and Working Examples The only direction or guidance present in the instant specification is the vague listing of diseases, disorders, and conditions applicant considers as treatable by the claimed compounds and the EC50’s and percent protein reduction of IKZF1, GSPT1, and SALL4 using a limited number of compounds of Formula (I). The specification does not show any examples where compounds of the claims were used to treat or prevent the full scope of disorders, diseases, or conditions in a subject mediated by cereblon, IKZF1, GSPT1, or SALL4 as set forth in claims, but merely demonstrates that certain compounds inhibit do reduce IKZF1, GSPT1, and SALL4 protein concentrations in a model assay. (See MPEP § 2164.02 (“Compliance with enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed… Lack of a working example, however is a factor to be considered, especially in a case involving an unpredictable and undeveloped art”.)
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what diseases, disorders, and conditions out of all disorders, diseases, or conditions in a subject mediated by cereblon, IKZF1, GSPT1, or SALL4 would be benefited (treated, prevented, or cured) and would furthermore then have to determine which of the claimed compounds in the instant invention would provide treatment and prevention of the claimed diseases.
A person having ordinary skill in the art at the time the invention was made would be faced with an undue amount of experimentation to use the pharmaceutical compositions for the full scope of the claimed intended uses.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
The specification fails to provide enough support of the broad use of the methods of administering compounds of the claims in the treatment or prevention of disorders, diseases, or conditions in a subject mediated by cereblon, IKZF1, GSPT1, or SALL4 as a result necessitation one of skill to perform an exhaustive search for which diseases can be treated or prevented by what compounds of the invention to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CAFC) 42 USPQ2d 1001, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent 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”.
Therefore in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compounds encompassed in the instant claims, with no assurance of success.
Allowable Subject Matter
Claims 40, 43-45, and 47-48 are allowed.
Close Prior Art Not Cited
Close prior art identified during the search is H. Lee Moffitt Cancer Center & Research Institute, Inc. (WO 2017/161119 A1, herein after “Moffitt”), which teaches small molecules against cereblon to enhance effector T cell function (abstract). Specifically, Moffitt teaches compounds of Formula II (page 38):
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And when L is absent, y is 0, x is 1, and the ---- bond is present or absent, partially maps to a compound of instant Formula (I). Markush groupings of R1, R3, R4, R5, and R8 overlap with instant variables R1a, R1b, R1c, R1d, Rd2, and Rd3. Though the genus of Formula II allows Ar to be an unsubstituted or substituted heteroaryl, the definition of heteroaryl disclosed by Moffitt refers to a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms (page 18, lines 25-26). Thus, the benzofuran of instant Formula (I) does not fall under this definition. There is no motivation, teaching, or suggestion in Moffitt, alone or in combination with the prior art, to modify the genus of Formula II to arrive at compounds of instant Formula (I).
Conclusion
Claims 40, 43-45, and 47-48 are allowed. Claims 41-42 and 46 are objected to. Claims 49-50 are rejected.
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.
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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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.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621