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 Status
Claims 1-3, 10-12, 15-17, 19-26, 37-56, 67-77, 79, 84 and 89 are pending.
Claims 16, 19, 21, 23, 26, 37, 39-56, 67-74, 84 and 89 are withdrawn pursuant to Applicant’s election of IC-23, without traverse, in the reply filed on January 20, 2026.
Claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 are active and subject to examination.
Claim Rejections – Withdrawn
The rejection of claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The rejection of claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
The rejection of claims 1-3, 10-12, 15, 24, 25, 75-77 and 79 under 35 U.S.C. 103 as being obvious over Dornan et al. (US 2023/0293716 A1) in view of Thompson (WO 2019/118884 A1) is withdrawn.
The above rejection was overcome by Applicant’s statement that the subject matter of Doman and the claimed invention were owned by the same person (Bolt Therapeutics) not later than the effective filing date of the claimed invention. The rejection is excepted under 35 U.S.C. § 102(b)(2)(C).
The provisional rejection of claims 1-3, 10-12, 15, 17, 24, 25, 75-77 and 79 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 11-22, 24-64, 66, 68-69, 71 and 74 of copending Application No. 17/923,541 (herein Dornan) in view of Thompson et al. (WO 2019118884 A1) is withdrawn.
The rejection is withdrawn as moot because Application No. 17/923,541 was abandoned.
Claim Rejections – 35 USC § 112(a) – Previously Presented
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.”
The rejection of claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 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 claim(s) contains 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 make and/or use the invention is maintained.
Response to Arguments
Applicant’s arguments filed June 16, 2026 have been fully considered but they are not persuasive.
First, the Applicant asserts that “the example linker-drug intermediates in Tables 2a and 2b at page 70 and twenty-four immunoconjugates in Tables 3a and 3b are a reasonable number of working example embodiments to enable the scope of claim 1.” (Remarks, p. 37). That characterization is not supported by the data presented in the tables. Tables 3a and 3b report a drug-to-antibody ratio (DAR) for each of IC-1 to IC-24 but report functional data for only three conjugates: IC-3, IC-7 and IC-22. The remaining twenty-one entries are accompanied by no activity data of any kind. The specification states that “Immunoconjugates of Tables 3a and 3b were tested utilizing methods described in Example 203 with the majority demonstrating activity.” (Spec., p. 96). This language expresses acknowledges that a subset of the exemplified conjugates did not perform as intended. The specification does not identify which conjugates failed, how many failed, what magnitude of response was treated as “activity,” or what properties distinguished the successful conjugates from the unsuccessful ones. As inoperative embodiments are present even within this deliberately selected set, the skilled artisan has no basis to predict which species would be success across the unbounded antibody genus of claim 1, for which no examples exist at all.
When a claimed genus includes inoperative embodiments, enablement turns on whether the skilled artisan can identify the operative embodiments without undue experimentation (See MPEP § 2164.08(b)). Here the specification provides no such means. It does not disclose which of the exemplified conjugates were inoperative, and it discloses no structure activity relationship, selection rule or predictive principle by which the skilled artisan could screen candidate conjugates other than by making and testing each one.
The three conjugates for which results are reported do not define a coherent subset. IC-3 employs PAZ-L-6 at DAR of 2.43; IC-7 employes PAZ-L-12 at a DAR of 2.37; IC-22 employs PAZ-L-28 at a DAR of 3.6. IC-3 and IC-7 use trastuzumab (HER2), while IC-23 uses 1-glf1 (TROP2). Conjugates prepared with the same antibody and closely comparable DARs are reported without any result (e.g. IC-1, IC-8, IC-9 and IC-23). Even when only a single dimension of the claim is varied, PAZ-L, one of ordinary skill in the art would not know the result. If one of ordinary skill in the art cannot predict the result when only the PAZ-L is varied among closely related species, it plainly cannot be predicted across the full scope of formula IIa and IIb, across the recited linker genus, or across the unrestricted antibody component.
Furthermore, Applicant argues that “[t]he scope of claim 1 is modest, being limited to novel 5-aminopyrazoloazepine moieties of formulas IIa and Ilb of only two types. Linker L is limited to specific embodiments.” This characterization is not accurate.
Formula IIa and IIb are generic scaffolds, not two compounds. Within each formula claim 1 recites:
X1, X2, and X3 are independently selected from eight alternatives, yielding 512 combinations of connector chemistry alone;
R1, R2, R3, and R4 are each independently selected from H, C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl, together with more than sixty additional recited groups spanning carbocyclyl, aryl, heteroaryl, and heterocyclyl containing moieties, many of which themselves contain a variable group R5 and R5a substituents, and may be optionally substituted with a list of dozens of substituents; and
L is selected from approximately 30 recited linker structures built from PEG, Gluc, and PEP.
The resulting genus is combinatorially enormous. That the core ring system is common to the genus does not make the genus small because it only shows the scaffold and not the number of compounds within the genus.
Moreover, the site at which the antibody is attached to the payload itself is an unrestricted variable. Claim 1 allows the linker-antibody group to be attached to any one of R1, R2, R3 or R4. The claim therefore encompasses four distinct conjugate architectures, which determine the spatial relationship between the antibody and the PAZ pharmacophore. Applicant’s own claim set treats these as distinct embodiments. Claim 22 separately recites attachment to R4. The Applicant also only exemplifies a narrow subgenus of the claimed genus. Tables 2a and 2b only show the linker attachment to R1 and R4. These examples also use a much smaller subset of X groups, R groups and linkers than is encompassed within the genus of claim 1.
Applicant’s assertion that the claims do not rely on any particular activity does not overcome the rejection. Applicant assert that “[w]hile variations in the antibody component can alter conjugation efficiency, stability, pharmacokinetics, immunogenicity, and therapeutic efficacy, the claims do not rely on any particular activity, conjugation yield, DAR, or property of the immunoconjugates.” (Remarks, p. 38). The enablement requirement of 35 U.S.C. § 112(a) requires that the specification teach the skilled artisan how to make and use the claimed invention (See MPEP § 2164.01). The utility disclosed for the claimed immunoconjugates is treatment of cancers susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism and is expressly claimed in claims 77 and 79. An immunoconjugate that does not elicit that response is not enabled for its disclosed use, whether or not the composition claims recite a functional limitation.
Applicant directs attention to the definitions of antibodies at pages 4-6 and 22-29, target antigens at pages 16-20 antibody sequences at pages 29-44, antibody embodiments at pages 202-22, linker-drug preparation at pages 121-141, and conjugation process at pages 141-143 (Remarks, p. 37). These disclosures are acknowledged. They describe what an antibody is, identify targets, and set forth synthetic conjugation chemistry. None of them addresses the deficiencies identified in the rejection, that is, what structural, biochemical or functional properties an antibody must possess to yield a functional immunoconjugate. The examples at pages 141-142 remain prophetic and are not working examples of completed, characterized conjugates.
The claimed genus is unbounded in the antibody dimension, encompasses hundreds of connector permutations and more than sixty R-group alternatives in the payload dimension, each with different variables, permits conjugation at any four of structurally distinct positions on that payload, and recites approximately thirty linker moieties each with their own variables. Against that scope, the record contains only three conjugates with reported activity, all sharing a single payload architecture and attachment geometry, together with an express acknowledgement that some of the exemplified conjugates did not demonstrate activity at all and no disclosed means of identifying which will express activity. Considering all of the Wands factors together, the specification does not reasonably enable one of ordinary skill in the art to make and use the full scope of the claimed invention without undue experimentation.
Reiterated Rejection
Claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 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 claim(s) contains 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 make and/or use the invention.
Claim Language at Issue
Claim 1 is directed towards an immunoconjugate of formula I:
PNG
media_image1.png
44
154
media_image1.png
Greyscale
, wherein PAZ is the 5-aminopyrazoloazepine moiety of formula IIa or IIb:
PNG
media_image2.png
126
505
media_image2.png
Greyscale
.
Claim 2 recites: The immunoconjugate of claim 1 wherein the antibody is an antibody construct that has an antigen binding domain that binds to a target selected from PD-L1, HER2, CEA, and TROP2.
Claim 3 recites: The immunoconjugate of claim 2 wherein the antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and sacituzumab.
Claims 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 are dependent on claim 1 and do not limit the scope of the claimed antibody.
Applicable Legal Standard – MPEP § 2164.01(a)
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. See Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (reversing the PTO’s determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The court held that the specification was enabling with respect to the claims at issue and found that “there was considerable direction and guidance” in the specification; there was “a high level of skill in the art at the time the application was filed;” and “all of the methods needed to practice the invention were well known.” 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that “it would not require undue experimentation to obtain antibodies needed to practice the claimed invention.” Id., 8 USPQ2d at 1407.
It is improper to conclude that a disclosure is not enabling based on an analysis of only one of the above factors while ignoring one or more of the others. The examiner’s analysis must consider all the evidence related to each of these factors, and any conclusion of nonenablement must be based on the evidence as a whole. 858 F.2d at 737, 740, 8 USPQ2d at 1404, 1407.
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. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Analysis Under Wands Factors
(1) Breadth of the Claims
The claims are drawn to an exceedingly broad genus of immunoconjugates.
Claim 1 is directed towards an immune conjugate of an TLR7/8 payload with any unspecified antibody. The claim encompasses immunoconjugates encompassing the entire universe of known and yet-to-be-discovered antibodies and antibody constructs- including full-length IgGs of all isotypes, antibody fragments, bispecific constructs, chimeric antigen receptors and any other construct falling within the specification’s broad definition of “antibody construct.” This represents an extraordinarily broad genus with no meaningful boundary on the antibody component.
Claim 2 recites immunoconjugates in which the antibody construct binds to any one of four structurally distinct targets: PD-L1, HER2, CEA and TROP2. These antigens are structurally and functionally diverse and each is expressed on different cells types and tumor types at varying densities.
Claim 3 further recites seven named antibodies (atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and Sacituzumab), each having structurally distinct properties, as well as open-ended categories of “biosimilar” or “biobetter” variants thereof. The “biobetter” category is defined in the specification to encompass antibody constructs with unspecified modifications that improve upon the listed properties (specification, p. 7). This language encompasses an indeterminate number of antibodies that have not yet been created, identified, or characterized, rendering the claim scope essentially unbounded in the antibody dimension.
The remaining claims do not attempt to narrow the breadth of the claimed antibodies.
(2) Nature of the Invention
The invention resides in immunoconjugates comprising antibodies conjugated to pyrazoloazepine TLR7/TLR8 agonist via linkers. The field of antibody-drug conjugates and immunoconjugates is widely recognized as a complex area of drug development in which the interplay among antibody identity, linker chemistry, payload, drug-to-antibody ratio, conjugation site, and target biology profoundly impacts the functional properties of the resulting conjugate. Minor structural variations in the antibody component can significantly alter conjugation efficiency, stability, pharmacokinetics, immunogenicity, and therapeutic efficacy. See Khongorzul et al. (Mol Cancer Res (2020) 18 (1): 3–19).
(3) State of the Prior Art
At the time of filing, the prior art recognized that immunoconjugate development is highly empirical. The conjugation of small-molecule payloads to antibodies can affect antibody folding, antigen binding affinity, Fc receptor engagement and pharmacokinetic behavior in unpredictable ways that are specific to the antibody being conjugated. Different antibodies, even those targeting the same antigen, have unique three-dimensional structural, lysine residue accessibility patterns, aggregation propensities, and thermal stabilities, each of which affects conjugation behavior and conjugation performance differently. The art has not established that successful conjugation and functional performance of an immunoconjugate with one antibody is predictive of success with a structurally distinct antibody, let alone an antibody targeting a different antigen or an antibody whose identity is unspecified. See Khongorzul et al. (Mol Cancer Res (2020) 18 (1): 3–19).
(4) Level of One of Ordinary Skill in the Art
One of ordinary skill in the art would have a PhD or equivalent experience in biochemistry, immunology, pharmacology, or a related field, with practical experience in antibody conjugation chemistry and immunoconjugate or ADC development. Such a person would be well aware that conjugation protocols and performance characteristics must be individually optimized and validated for each antibody, and that successful conjugation of a payload to one antibody does not guarantee that the same chemistry will produce a functional conjugate with a different antibody.
(5) Level of Predictability in the Art
The level of predictability in the immunoconjugate art is low. As recognized by the Federal Circuit, the biological and chemical arts are generally considered unpredictable. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). In the specific context of immunoconjugates, the following properties are unpredictable across different antibodies: (a) conjugation efficiency and site selectivity, as different antibodies present different amino acid ratios and microenvironments for conjugation; (b) drug-to-antibody ratio (DAR) distribution and homogeneity; (c) retention of antigen binding activity post conjugation; (d) conjugate stability in serum and in storage; (e) Fc mediated effector functions after conjugation; (f) pharmacokinetic and biodistribution profiles; and (g) in vivo efficacy and safety. See Khongorzul et al. (Mol Cancer Res (2020) 18 (1): 3–19). The specification’s reliance on TLR7/TLR8 agonists as the payload adds an additional layer of unpredictability, as the immunostimulatory activity of the conjugate depends on the delivery to the correct intracellular compartment following receptor-mediated endocytosis, a process that is inherently antibody and target dependent. These unpredictabilities are amplified when the antibody component is entirely unrestricted, as in claim 1.
(6) Amount of Direction Provided by the Inventor
The Specification provides detailed descriptions of the pyrazoloazepine compounds, linker chemistry, and general conjugation methodologies, including the use of sulfo-tetrafluorophenyl ester (S-TFP) activated linkers for lysine conjugation (Specification, p. 50-90). The specification also provides general definitions of certain antibody targets and named antibodies (id., p. 16-43).
The specification, however, does not provide guidance sufficient to enable the skilled artisan to practice the full scope of the claims. Specifically: (a) with respect to claim 1, the specification does not provide any direction for selecting an appropriate antibody from the unlimited genus encompassed by the claim, nor does it address the structural, biochemical, or functional requirements that an antibody must satisfy to yield a functional pyrazoloazepine immunoconjugate; (b) with respect to claim 2, the specification does not provide specific guidance for optimizing conjugation to antibodies targeting each of the four recited antigens, nor does it address whether conjugation affects the binding affinity or functional activity of the antibodies directed to each of these distinct targets; (c) With respect to claim 3, the specification does not provide specific conjugation protocols or characterization data for each of the seven named antibodies.
(7) Existence of Working Examples
The Specification provides working examples demonstrating the synthesis of pyrazoloazepine compounds, linker intermediates, and TLR7/TLR8 agonist activity of unconjugated compounds (Specification, p. 105-140, fig. 1-2). However, the specification does not include working examples of completed, characterized immunoconjugates with each of the seven named antibodies in claim 3, with antibodies targeting each of the four antigens in claim 2, or with a representative set of structurally diverse antibodies sufficient to demonstrate the conjugation chemistry is generalizable to the unlimited antibody genus of claim 1. The specification only provides hypothetical examples of antibody-drug conjugation (Specification, p. 141-142). Tables 3a and 3b only demonstrate activity for three similar immunoconjugates using two antibodies (trastuzumab and 1-Glf) (id., p. 96-97).
The absence of working examples across the breadth of the claimed antibodies is particularly significant in view of the known unpredictability of immunoconjugate chemistry. Working examples with one or a limited number of antibodies cannot be reasonably extrapolated to predict successful preparation and functional performance of conjugates made with structurally distinct antibodies targeting different antigens, much less the unlimited genus of claim 1. See In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993) (in unpredictable arts, enablement of a broad genus typically requires more than a few working examples within a genus).
(8) Quantity of Experimentation Needed
In view of the above factors, the quantity of experimentation required to practice the full scope of the invention of claims 1-3 would be undue. For each antibody encompassed by the claims, the person of ordinary skill in the art would need to: (a) optimize conjugation conditions (buffer, pH, molar ratios, reaction time) for the specific antibody; (b) characterize the resulting conjugates for drug-antibody-ratio, site distribution, aggregation, and purity; (c) verify retention of antigen binding activity; (d) assess conjugate stability in vivo and under storage conditions; (e) evaluate TLR7/TLR8 agonist activity of the conjugated payload; and (f) determine the in vitro/ in vivo functional performance.
For claim 1, this optimization would need to be performed without any boundary on the antibody component, meaning the skilled artisan would face an open-ended research program of unpredictable scope. For claim 2, the experimentation would need to be repeated for antibodies targeting each of the four distinct antigens. For claim 3, it would need to be independently completed for each of the seven named antibodies. The cumulative experimentation required is extensive, uncertain in outcome, and constitutes undue experimentation.
Conclusion
Considering all of the Wands factors together, the specification does not reasonably enable one of ordinary skill in the art to make and use the full scope of the claimed immunoconjugates without undue experimentation. Independent claim 1 presents the most significant enablement deficiency because it encompasses immunoconjugates with any antibody, an effectively unbounded genus. The specification does not provide sufficient direction, working examples, or predictive principles to enable the skilled artisan to select any antibody and produce functional pyrazoloazepine immunoconjugates without extensive, unpredictable experimentation.
Dependent claims 2 and 3 do not cure this deficiency. Although they narrow the antibody component, they still encompass inmunoconjugates with multiple structurally and functionally diverse antibodies targeting distinct antigens, and claim 3 further includes the open-ended biosimilar and biobetter language that reintroduces an undefined and unbounded scope. The art of immunoconjugate development is highly unpredictable, the specification provides insufficient direction specific to each claimed antibody and target, working examples covering the full claim scope are absent, and the experimentation needed to bridge these gaps would be extensive, uncertain and unduly burdensome.
Conclusion
No claim is found to be allowable.
THIS ACTION IS MADE FINAL. 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 extension fee 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 HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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 Lundgren can be reached on (571) 272-5541. 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 86-217-9197 (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.
/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
Prosecution Insights