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 .
Claim of Foreign Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application CH 00385/21, filed on April 14, 2021. It is noted, however, that applicant has not filed a certified copy of the Swiss application as required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group I, corresponding to claims 1-15, in the reply filed on June 18, 2026, is acknowledged. Applicant further elected compound 42. The elected species is free of the prior art, as well as the Formula (I) set forth in claim 1.
Status of the Claims
Claims 1-15, 19, 27, 35, and 43-44 are pending. Claims 19, 27, 35, 43, and 44 are withdrawn. Claims 1-15 are examined.
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 1-10 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the compounds set forth in the instant Specification, are not considered enabled for the other compounds encompassed by Formula (I) of claim 1. 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.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to act as modulators of TRPML.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to act as modulators of cereblon. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. As noted by Hall et al., “Topological Quantitative Structure–Activity Relationship Applications: Structure Information Representation in Drug Discovery,” Comprehensive Medicinal Chemistry II, Vol 4, 2007, pp537-574, there is a role of structure information representation in drug development. This is based on molecular structure being related to biological activity in structure-activity relationships (QSAR) models. Similarly, structure can be used as a basis to screen a structure library to determine by similarity those that have potential for further development. The basis for this it that structure is correlated to function.
As such, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects.
Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation. A low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification discloses 75 compound In Table 1, which are cereblon modulators. See pp. 117-121. Table 2 provides the efficacy of these compounds in the form of IC50 values for many of those synthesized compounds. The values for IC50 modulation ranges from less than 600 nM to greater than 1900 nM, represented by numbers A through D. Further, there are some including compounds 64-69 that have no data. The values for similarly structured compounds range from A to D. There is no specificity with regard to what less than 600 nM means or what greater than 1900 means.
Of these examples, there are common structural features among them. For example, L2 and X1 are similar for each example. L2 is a bond in each example. Similarly, X1 is aryl or pyridine in all examples.
However, X1 is claimed to be one of the following:
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Even further, despite the similar structures of compounds, the IC50 values presented in Table 2 can be significantly variable. For example, compound 5 has a value of “B” while compound 4 has a value of “D”. This means that compound 4 has an IC50 value above 1900 nM (which could be 5000 or 10,000 or greater) and compound 5 has a value of 600 to 1200. The structures are shown below.
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The sole distinction here is a Cl substituted with an -OMe-, which drastically alters IC50 for the compound despite variables L1, L2, X1, L3, and X2 being identical. The alteration in “Y” accounts for a substantial difference in IC50 and it shows that the alteration of a single atom or two can drastically alter the efficacy of the compound.
Y is shown in the examples to be a methyl, fluorine or -OMe in almost all of the examples. CN, Br, Cl, is used in a single example and fluorine or -OMe- are used in 72/75 examples.
Table 3 provides activity for GSPT1 degradation. Some compounds have a value of “D”, including 70, 72, and 73. Others gave a value of C (i.e., 58 and 68). The structural permutations do no make it clear why these compounds have substantially different values from others.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
As to the first inquiry, as discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to as cereblon modulators and degraders of GSPT1. Considering that Formula (I) encompasses potentially tens of thousands of compound species or more, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses numerous similarly structured compound species encompassed by Formula (I) as recited by the claims. However, the data provided includes substantial potency variability with respect to IC50 values of those compounds.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to act as modulators of cereblon and degraders of GSPT1. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formula (I) with respect to the disclosure and data. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the thousands of compounds encompassed by Formula (I). Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme.
As noted above, there are common structural features among them. For example L2 is a bond and X1 is aryl or pyridine in all examples. Further, even when L1, L2, X1, L3, and X2 are identical a distinction in variable “Y” can account for a substantial difference in IC50 values. See Table 2.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or Despite this, the instant claims include thousands of permutations and do not require structural limitations that are present in all or substantially all of the structures of the embodiments shown in the Specification.
The above are examples of limited variability among the combinations despite the Specification also showing that minor structural changes can drastically alter the efficacy of a compound.
Not only are the synthesized compounds limited substantially in their structures relative to the breadth of the claims, but the variability and data to any degree is lacking with respect to IC50 cereblon modulator activity.
Thus, in order to identify usable compounds of Formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 75 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (I) for in vitro testing. Given the unpredictability of the chemical arts, it is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) (i.e., those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of millions, and potentially billions, of claimed compounds encompassed by Formula (I) are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Non-Provisional
Claims 1-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11,912,682. Although the claims at issue are not identical, they are not patentably distinct from each other because the compound recited in claim 1 of the ‘682 patent is a compound that falls within the scope of independent claim 1 and it is an isomer and bioisostere of compounds that fall within the scope of dependent claim 14. The following compound is claimed on page 14 of the instant claims. A single fluorine in the position of “Y” distinguishes.
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Claims 1-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,391,663. Although the claims at issue are not identical, they are not patentably distinct from each other because the compound recited in claim 1 of the ‘663 patent is a compound that falls within the scope of independent claim 1 and it is an isomer and bioisostere of compounds that fall within the scope of dependent claim 14. The following compound is claimed on page 14 of the instant claims. The claimed moiety in the position of L2-X2 is shown as the 4th moiety down in column 491 of the ‘663 patent, shown below.
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and the remainder of the compound is as claimed, shown below from claim 1.
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.
As such, the claims encompass the same compounds.
Provisional
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of copending Application No. 18/471,563. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘563 patent include claimed compounds. For example, claim 31 includes the same core presently claimed. Further, claim 7 includes the following:
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, wherein W1 is defined to be:
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. This is moiety is also claimed on page 9 of the instant claims in the third row down, third compound listed. The claims overlap.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-48 of copending Application No. 19/236,429. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘429 patent include claimed compounds. Claim 121 on page 9 of the ‘429 patent is an isomer or bioisostere with a single fluorine difference over compounds claimed in instant claim 14, including the following:
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or the following moiety of instant claim 13:
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Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27-31 of copending Application No. 18/271,954. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘954 patent include claimed compounds. Claim 31 of the ‘954 patent is an isomer or bioisostere with a single fluorine difference over compounds claimed in instant claim 14, including the following:
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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
Prosecution Insights