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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted in Aug. 30, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-3, 10-26, 37-56, 67-77, 79, 84 and 89 are pending.
Applicant’s election without traverse of the immunoconjugate, IC-23, reading on claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79, in the reply filed on January 20, 2026 is acknowledged.1
Claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 are currently active and subject to examination. Claims 13-14, 16, 18-21, 23, 26, 37, 39-56, 67-74, 84 and 89 are withdrawn.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
“(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
“The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.”
Claims 1-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 are 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 1 is directed towards an immunoconjugate of formula I:
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, wherein PAZ is the 5-aminopyrazoloazepine moiety of formula IIa or IIb:
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.
One of ordinary skill in the art cannot determine the metes and bounds of the claim because it is unclear what substituents are allowed. For example, R1, R2, R3, and R4, are defined as follows:
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.
The above appears to define the substituents for e.g. the C1-C12 alkyl by saying that the alkyl is substituted by…, but the claim then doubly defines the substituents for these groups:
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Appropriate correction is required.
Claims 2-3, 10-12, 15, 17, 22, 24, 25, 38, 75-77 and 79 depend from claim 1 and do not resolve this ambiguity and are therefore also indefinite.
One of ordinary skill in the art cannot determine the metes and bounds of claim 3 because it is unclear what alternatives are encompassed by the claim. The claim sets forth a list of alternatives from a closed group “selected from the group consisting of” but then recites or “biosimilars or biobetters thereof”
[A]lternatives may be set forth as "a material selected from the group consisting of A, B, and C"… A Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members. Abbott Labs., 334 F.3d at 1280, 67 USPQ2d at 1196. If a Markush grouping requires a material selected from an open list of alternatives (e.g., selected from the group "comprising" or "consisting essentially of" the recited alternatives), the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022) (each independent claim recites "a selection from the group comprising a person, an animal, an animated character, a creature, an alien, a toy, a structure, a vegetable, and a fruit." … (emphasis added). "Given the breadth of variation among the specified alternatives and the use of the open-ended word ’comprising’ to define the scope of the list, we affirm the Board's conclusion that the pending claims recite improper Markush language and are indefinite under § 112(b).").
MPEP § 2173.05(h).
Appropriate correction is required.
Claim Rejections – 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
Claims 12, 13, 17, 22, and 38 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 12, 13, 17, 22 and 38 include definitions for R1-R4 which are not consistent with claim 1. For example, claim 1 does not state that R1-R4 can be O-alkyl as in claims 12, 15 and 17. In claims 13, 17 and 22, R1-R4 are
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and
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which are the substituents on R1-R4 in claim 1, but do not include the actual definitions of R1-R4.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 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:
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, wherein PAZ is the 5-aminopyrazoloazepine moiety of formula IIa or IIb:
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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 or a biosimilar or a biobetter thereof.
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, nor does it describe how to identify, produce or conjugate “biosimilar” or “biobetter” variants.
(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).
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, with still further experimentation needed for the undefined biosimilar and biobetter antibodies, which would first require designing, producing and characterizing the antibody constructs themselves before conjugation could be attempted. 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.
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
“A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1-3, 10-12, 15, 24, 25, 75-77 and 79 is/are rejected 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) (of record, cited in the last office action).
The applied reference has common inventor(s) and assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claim 1 is directed towards an immunoconjugate of formula I:
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, wherein PAZ is the 5-aminopyrazoloazepine moiety of formula IIa or IIb:
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One of ordinary skill in the art would have a reasonable expectation of success to obtain an immunoconjugate of formula I as in claim 1 because such generic compounds are known in the art.
For example, Dornan teaches immunoconjugates of formula I:
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(Dornan, Specification, para. [0478]), wherein Ims is an immunostimulatory compound selected from a compound of formula Ie and If:
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Dornan, Specification, para. [0483].
The Ims compound specifically includes amino-pyrazoloazepines of formula e and f:
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Dornan, Specification, para. [0343].
Dornan teaches substituents and linkers which overlap those of claim 1 of the instant invention.
Therefore, claim 1 was prima facie obvious at the time of filing.
Claim 2 is directed towards 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.
One of ordinary skill in the art would have a reasonable expectation of success to use an antibody 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 because these immunoconjugates are known in the art.
For example, Dornan teaches that the antibody is an antibody construct may comprise an antigen binding domain of an anti-PD-L1 antibody, anti-HER2 antibody or an anti-CEA antibody (Dornan, Specification, para. [0102]) or TROP2 (id., para. [0317]).
Therefore, claim 2 was prima facie obvious at the time of filing.
Claim 3 is directed towards the immunoconjugate of claim 2, wherein the antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and Sacituzumab, or a biosimilar or a biobetter thereof.
One of ordinary skill in the art would have a reasonable expectation of success to formulate the immunoconjugate with an antibody selected from the group consisting of tezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and Sacituzumab because immunoconjugates formulated with these antibodies are known in the art.
For example, Dornan teaches that the antibody is atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab (Dornan, Specification, para. [0473-0475]) as well as Sacituzumab (id., para. [0321]).
Therefore, claim 3 was prima facie obvious at the time of filing.
Claim 10 is directed towards the immunoconjugate of claim 1, wherein X1 is a bond and R1 is H. Claim 11 is directed towards the immune conjugate of claim 1, wherein X2 is a bond, and R2 is C1-8 alkyl. Claim 12 is directed towards the immunoconjugate of claim 1, wherein X2 and X3 are bonds and R2 and R3 are selected from
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Claim 15 is directed towards the immunoconjugate of claim 12, wherein R2 and R3 are
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One of ordinary skill in the art would have a reasonable expectation of success to formulate an immunoconjugate as in claims 10-12 and 15 because Dornan teaches these substituents generically (Dornan, Specification, para. [0484] and [0553]) and similar species with these specific substituents. For example:
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Dornan, Specification, para. [0713].
Therefore, claims 10-12 and 15 were prima facie obvious at the time of filing.
Claim 24 is directed towards the immunoconjugate of claim 1, wherein L is connected to a cysteine thiol of the antibody.
One of ordinary skill in the art would have a reasonable expectation of success to connect L to a cysteine thiol of the antibody because this attachment is known in the art. For example, Dornan teaches attachment to a cysteine thiol of the antibody (Dornan, Specification, para. [0652]).
Therefore, claim 24 was prima facie obvious at the time of filing.
Claim 25 recites is directed towards the immunoconjugate of claim 1, wherein for the PEG, m is 1 or 2 and n is an integer from 2 to 10. One of ordinary skill in the art would have a reasonable expectation of success to use a PEG wherein m is 1 or 2 and n is an integer from 2 to 10 because these linkers are commonly known in the art.
For example, Dornan specifically prefers a PEG wherein m is 2 and n is 10 (Dornan, Specification, para. [0464]) and presents an example with this PEG (II-3; id., Table 1A, p. 36).
Therefore, claim 25 was prima facie obvious at the time of filing.
Claim 75 is directed towards the same subject matter as claim 1 and is rejected on the same basis as claim 1.
Claim 76 is directed towards a pharmaceutical composition comprising an immunoconjugate according to claim 1, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient.
One of ordinary skill in the art would have a reasonable expectation of success to formulate a pharmaceutical composition comprising an immunoconjugate of claim 1, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient because such compositions are known in the art.
For example, Dornan teaches a pharmaceutical composition comprising an immunoconjugate of claim 1, and one or more pharmaceutically acceptable carriers (Dornan, Specification, para. [0657]).
Therefore, claim 76 was prima facie obvious at the time of filing.
Claim 77 is directed towards a method of treating cancer comprising administering a pharmaceutical composition of claim 76 to a patient in need thereof, wherein the cancer is selected from cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, and breast cancer, and is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism. Claim 79 is directed towards the method of claim 77, wherein the cancer is selected from a PD-L1-expressing cancer, a HER2-expressing cancer, a CEA-expressing cancer, and a TROP2-expressing cancer.
One of ordinary skill in the art would have a reasonable expectation of success to treat cancer by the above method because it is known in the art that the immunoconjugate of claim 1 can be used in such a method. For example, Dornan teaches a method for treating cancer comprising administering a therapeutically effective amount of an immunoconjugate (e.g. a composition as described above) to a subject in need thereof (Dornan, Specification, para. [0664]), wherein the cancer is breast cancer, colon cancer, lung cancer, renal cancer, pancreatic cancer, gastric cancer, or esophageal cancer (id., para. [0686]), wherein the cancer and the cancer is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 (id., para. [0687]). Dornan indicates that the tumor expresses PD-L1, HER2, CEA, and TROP2 as the method can include administering an immunoconjugate capable of binding HER2, PD-L1 and CEA or tumors over-expressing CEA (id., para. [0686]).
Therefore, claims 77 and 79 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Nonstatutory 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.
Claim 1-3, 10-12, 15, 17, 24, 25, 75-77 and 79 is/are provisionally rejected 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) (of record, cited in the last office action).
Claim 1 is directed towards an immunoconjugate of formula I:
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, wherein PAZ is the 5-aminopyrazoloazepine moiety of formula IIa or IIb:
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.
Dornan claims immunoconjugates of formula I:
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(Dornan, claim 13), wherein Ims is an immunostimulatory compound selected from a compound of formula Ie and If:
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Dornan, claim 15. The definitions for X1-X4 and R1-R4 significantly overlap with the claimed formula 1.
One of ordinary skill in the art would have a reasonable expectation of success to narrow the genus to amino-pyrazoloazepines because amino-arylazepines are commonly known in the immunoconjugate arts.
For example, Dornan specifically claims amino-arylazepines compounds wherein X5 is a bond and R5 is H:
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(Dornan, claim 42).
For example, Thompson teaches amino-ayrlazepine immunoconjugates:
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Thompson, Specification, p. 53.
Therefore, claim 1 is rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 2 is directed towards 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 is directed towards the immunoconjugate of claim 2, wherein the antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and Sacituzumab, or a biosimilar or a biobetter thereof.
Dornan claims the immunoconjugate wherein the antibody binds to a target selected from PD-L1, HER2, CEA and TROP2 (claim 3) and wherein the antibody is selected from the group consisting of atezolizumab, durvalumab, avelumab, trastuzumab, pertuzumab, labetuzumab, and Sacituzumab, or a biosimilar or a biobetter thereof (claim 4).
Therefore, claims 2-3 are rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 10 is directed towards the immunoconjugate of claim 1, wherein X1 is a bond and R1 is H. Claim 11 is directed towards the immune conjugate of claim 1, wherein X2 is a bond, and R2 is C1-8 alkyl. Claim 12 is directed towards the immunoconjugate of claim 1, wherein X2 and X3 are bonds and R2 and R3 are selected from
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Claim 15 is directed towards the immunoconjugate of claim 12, wherein R2 and R3 are
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Claim 17 recites: The immunoconjugate of claim 12 wherein R2 is -CH2CH2CH3 and R3 is -OCH2CH3.
One of ordinary skill in the art would have a reasonable expectation of success to formulate an immunoconjugate as in claims 10-12 and 15 because Dornan specifically claims compounds in this subgenus and similar compounds are commonly known in the art:
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Also, for example, see the compounds of Thompson (Thompson, Specification, p. 53-56).
Therefore, claims 10-12, 15 and 17 are rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 24 is directed towards the immunoconjugate of claim 1, wherein L is connected to a cysteine thiol of the antibody.
While Dornan does not claim wherein L is connected to a cysteine thiol of the antibody, one of ordinary skill in the art would have a reasonable expectation of success to connect L to a cysteine thiol of the antibody because this attachment is known in the art. For example, Thompson teaches that the linker can be connected to a cysteine thiol of the antibody (Thompson, Specification, para. [0245]).
Therefore, claim 24 is rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 25 recites is directed towards the immunoconjugate of claim 1, wherein for the PEG, m is 1 or 2 and n is an integer from 2 to 10. One of ordinary skill in the art would have a reasonable expectation of success to use a PEG wherein m is 1 or 2 and n is an integer from 2 to 10 because Dornan claims PEGs wherein m is wherein m is 2 and n is 10 (claim 55).
Therefore, claim 25 is rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 75 is directed towards the same subject matter as claim 1 and is rejected on the same basis as claim 1.
Claim 76 is directed towards a pharmaceutical composition comprising an immunoconjugate according to claim 1, and one or more pharmaceutically acceptable diluent, vehicle, carrier or excipient.
Dornan claims a pharmaceutical composition comprising an immunoconjugate of claim 1, and one or more pharmaceutically acceptable carriers (claim 66).
Therefore, claim 76 is rejected on the grounds of obviousness type nonstatutory double patenting.
Claim 77 is directed towards a method of treating cancer comprising administering a pharmaceutical composition of claim 76 to a patient in need thereof, wherein the cancer is selected from cervical cancer, endometrial cancer, ovarian cancer, prostate cancer, pancreatic cancer, esophageal cancer, bladder cancer, urinary tract cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, Merkel cell carcinoma, colon cancer, colorectal cancer, gastric cancer, and breast cancer, and is susceptible to a pro-inflammatory response induced by TLR7 and/or TLR8 agonism. Claim 79 is directed towards the method of claim 77, wherein the cancer is selected from a PD-L1-expressing cancer, a HER2-expressing cancer, a CEA-expressing cancer, and a TROP2-expressing cancer.
One of ordinary skill in the art would have a reasonable expectation of success to perform the claimed methods because Dornan claims:
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Therefore, claims 77 and 79 are rejected on the grounds of obviousness type nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
1 Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).