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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-5, 7-9, 11, 13-20, and 24-25) and the species listed below in the reply filed on 01/30/2026 is acknowledged.
Elected Species:
An antibody for the targeting agent, wherein the antibody target is HER2.
X is NH.
Y is C=O.
Q is -CH2CH2O(CH2CH2O)7CH2CH2-.
R is H.
Z is as depicted in compound (13) wherein -AA-H represents the side chain of the amino acid 2,3-diaminopropionic acid, L4 is a group of formula (x), V1 is -(C=O)-C=N-OCH2(C=O)-, X1 is NH, m is 0, X2 is O, A is a bond, X’ is NH, Q’ is
-CH2CH2O(CH2CH2O)10CH2CH2-, Y’ is O, R’ is CH3, p is 2, X3 is O, L’ is a bond, V2 is -Val-Cit-PAB-(C=O)-, and B is small molecule drug SN-38.
The full structure of the elected species, in view of the above, is as shown below.
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Claim Status
Claims 6, 10, 12, 21, and 23 have been cancelled, as requested in the amendment filed on 01/30/2026. Following the amendment, claims 1-5, 7-9, 11, 13-20, 22, and 24-25 are pending in the instant application.
Claim 22 stands as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and claims 16-17 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species of invention in the Response filed 01/30/2026, there being no allowable generic or linking claim.
Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. It is further noted that the certified copy of the foreign priority document is in English, and therefore the claim to foreign priority has been perfected.
Claims 1-5, 7-9, 11, 13-20, and 24-25 have an effective filing date of May 27, 2020 corresponding to GB2007926.5, as the claim to foreign priority has been perfected.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/23/2022, 05/30/2024, 01/06/2025, and 03/21/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1 and 24 are objected to because of the following informalities: the claim lists antibody-drug conjugate components in a list using (i), (ii), and (iii), but also designates structures within the claim as (i), (ii), (iii), (iv), and (v). It is recommended that Applicant amend the claim such that the list designating antibody-drug conjugate components rely on characters different from those of the listed structures. For example, the list of the components may be listed as (a), (b), (c) and the structures identified by (i), (ii), (iii), (iv), and (v). Appropriate correction is required.
Claim 15 is objected to because of the following informalities: the bulleted list relies on the same characters; the first bulleted limitation is designated as (a) and refers to Z being a group of formula (ii), whereas the second bulleted limitation is also designated as (a) and refers to Z being a group of formula (iv). Appropriate correction is required.
Claim Rejections - 35 USC § 112 - Improper Markush
Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of antibody-drug conjugates is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: (i) the antibody-drug conjugate generically requires any antibody or antigen-binding fragment thereof; (ii) the polymer structure identified by Formula (I) has multiple possible structure variations; (iii) the polymer-antibody linker is generically recited and thus is drawn to any linker that covalently bonds both the polymer of Formula (I) and the antibody. With regard to (i), any antibody or antigen-binding fragment thereof may be used, encompassing an antibody binding to any antigen (i.e., cancer-association, autoimmune associated, etc.), and thus the antibodies encompassed may have any possible biological function and/or may be implicated in pathologically distinct diseases, disorders, and conditions. Regarding (ii), it is specifically noted that Formula (I) structural component Z may represented by one of formulas (i)-(v), wherein it specifically noted that each formula comprises different structural elements with variable chemical properties/features; for example, formulas (i)-(v) are defined by (a) different possible amino acid side chains (i.e., -AA-) which may be divalent or trivalent and may have chemically diverse properties, (b) may or may not comprise linking groups, wherein said linking groups are generically recited and could comprise chemically/functionally different moieties (e.g., cleavable vs. non-cleavable elements), and (c) biologically active moieties which are generically recited and therefore may have any biological activity/mechanism of action. With regard to (iii), it is specifically noted that any linker that covalently bonds both the polymer of Formula (I) and the antibody is encompassed, and could comprise chemically/functionally different moieties (e.g., cleavable vs. non-cleavable elements). The variability among the recited structural elements and subsequently the variability encompassed by their possible combinations yield antibody-drug conjugates that do not share both a single structural similarity and a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-5, 7-9, 11, 13-15, 18-20, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
With regard to independent claims 1 and 24, the claims are drawn to a genus of antibody-drug conjugates (ADCs) which comprise (i) any antibody or antigen-binding fragment thereof; (ii) a polymer structure identified by Formula (I); and (iii) a polymer-antibody linker that covalently bonds both the polymer of Formula (I) and the antibody. With regard to (i), any antibody or antigen-binding fragment thereof may be used, encompassing an antibody binding to any antigen (i.e., cancer-association, autoimmune associated, etc.), and thus the antibodies encompassed may have any possible biological function and/or may be implicated in pathologically distinct diseases, disorders, and conditions. Regarding (ii), it is specifically noted that Formula (I) structural component Z may represented by one of formulas (i)-(v), wherein it specifically noted that each formula comprises different structural elements with variable chemical properties/features; for example, formulas (i)-(v) are defined by (a) different possible amino acid side chains (i.e., -AA-) which may be divalent or trivalent and may have chemically diverse properties, (b) may or may not comprise linking groups, wherein said linking groups are generically recited and could comprise chemically/functionally different moieties (e.g., cleavable vs. non-cleavable elements), and (c) biologically active moieties which are generically recited and therefore may have any biological activity/mechanism of action. With regard to (iii), it is specifically noted that any linker that covalently bonds both the polymer of Formula (I) and the antibody is encompassed, and could comprise chemically/functionally different moieties (e.g., cleavable vs. non-cleavable elements). It is noted that within the Examples provided on Pages 102-132 of the instant specification, Applicant discloses a total of four species of ADCs that are adequately described such that the exact structure of the ADCs is disclosed (i.e., the antibodies are specifically identified (i.e., trastuzumab) and the polymer and polymer-antibody linker structures are fully provided). However, even though Applicant has disclosed four species of ADCs, Applicant is claiming a large and structurally diverse genus of ADCs, each of which can comprise (i) any antibody, (ii) one of numerous possible polymer structures of Formula (I), and (iii) any polymer-antibody linker that covalently bonds both the polymer of Formula (I) and the antibody. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which combinations of the recited Formula (I) structural elements, antibodies, and polymer-antibody linkers yield ADCs with desirable properties that are functional. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As previously indicated, Applicant has disclosed four species within the genus claimed. However, given the large number of species encompassed by the genus (thousands of possible ADCs) claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said numerous adequately described species is not sufficiently representative of the entire genus.
Furthermore, Applicant has not disclosed relevant, identifying structural elements/characteristics of antibodies, polymers of Formula (I), and/or the polymer-antibody linker (and combinations thereof) which yield ADCs with desirable properties that are functional. It is well-known in the art that linker components, structures, and subsequently chemical properties largely influence ADC pharmacokinetics, including successful targeted delivery and efficacy while antibody targets impact that pathologies that may be targeted with a given ADC. Absent a description of the at least minimal structural features correlating with ADCs with desirable properties that are functional, which are shared by members of a genus of ADCs, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which components (and combinations thereof) may be utilized such that the resultant ADCs have desirable properties and are functional.
Although screening techniques can be used to identify ADCs that possess the desired characteristics/functionality, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.”
Accordingly given the difficulty associated with predicting ADC structural elements and their subsequent combinations that yield ADCs with desirable properties that are functional, and given the lack of particularity with which the ADCs are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
Claims 2-5, 7-9, 11, 13-15, 18-20, and 25 are included in this rejection as they depend from/incorporate claim 1 or claim 24.
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 1-5, 7-9, 11, 13-15, 18, 20, and 24-25 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.
Regarding claims 1-5, 7-9, 11, 13-15, 18, 20, and 24-25, the claims are regarded as indefinite as the structural arrangement between the antibody or antigen-binding fragment thereof, polymer of Formula (I), and the polymer-antibody linker is not set forth by the claims. The polymer of Formula (I) is divalent (see independent claims 1 and 24), but the above-listed claims do not structurally set forth what the polymer is bound to, besides the antibody or antigen-binding fragment thereof and the polymer-antibody linker that links the antibody to the polymer. Thus, the claims indicate that the polymer-antibody linker and antibody/antigen-binding fragment thereof are bound to one side of the polymer, but it is unclear what, if anything, is bound to the remaining open valency.
With regard to claims 2, 8, 11, 13, 15, and 18, the relationship between, for example, formulas (ii) and (vi) is unclear. Specifically, it is noted that based on the definitions of the structural components of formulas (ii) and (vi) (see, for example, claim 15) the structures of formulas (ii) and (vi) are distinct, wherein the structures encompassed by formula (vi) cannot be derived based on the definitions of structural components of formula (ii). The claims are therefore considered indefinite as the metes and bounds of the claim cannot be distinguished due to the lack of clarity regarding how formula (vi) is derived from/relates to formula (ii).
With regard to claims 4 and 15, the claims recite the limitations (1) "L" in line 2 and (2) “Z is a group of formula (vi) and L4 is a linker moiety of formula (x) or (xi)” (see page 11 of claims). There is insufficient antecedent basis for these limitations in the claims. Regarding both claims 4 and 15, it is noted that there is no recitation of formula (vi), and therefore no recitation of L4, in claim 1.
With regard to claim 5, the claim recites “sulfone reagents that are Julia-Kocienski like”, however it is unclear as to what the metes and bounds of such a limitation are, as the specification does not provide one of ordinary skill in the art with a clear definition of what sulfone reagents would be considered “Julia-Kocienski like” and would be sufficient for the purposes of the invention.
Regarding claims 8-9, 11, 13-15, and 18, the phrase(s) "preferably" and/or “e.g.” render the claims indefinite because it is unclear whether the limitation(s) following the phrase(s) are part of the claimed invention. For example, claim 8 recites “wherein Z is a group of formula (vi), (vii), (viii) or (ix) and X' is O or NH and Y' is O or NH, preferably wherein X' is NH and Y' is O” (emphasis added); as presented it is unclear whether the limitation following the recitation of “preferably” is a required feature, or if the recited preferential limitation is merely exemplary and therefore not required. See MPEP § 2173.05(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 2, 8, 11, 13, 15, and 18 are 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 2, 8, 11, and 13 fail to further limit the subject matter of the claim upon which they depend (i.e., claim 1) because the claims are broader in scope than the claim from which they depend. Claim 1 recites that each Z of Formula (I) is independently selected from a group of formula (i), (ii), (iii), (iv), or (v). Claims 2, 8, 11, and 13 all recite and/or are drawn to: the group of formula (ii) being a group of formula (vi); the group of formula (iii) being a group of formula (vii); the group of formula (iv) being a group of formula (viii); and/or the group of formula (v) being a group of formula (ix). It is specifically noted that formulas (vi)-(ix) all recite additional structural components not recited/required in the structures of formulas (ii)-(v), and as such the structures of formulas (vi)-(ix) structurally redefine Z and are therefore considered to be broader than that of formulas (ii)-(v) recited in independent claim 1. Thus, claims 2, 8, 11, and 13 fail to further limit the subject matter of the claim upon which they depend (i.e., claim 1) because the claims are broader in scope that the claim from which they depend. Additionally, based on the definitions of the structural components of formulas (ii)-(v) and (vi)-(ix) in claim 15, for example, it is noted that the structures of formulas (ii)-(v) and (vi)-(ix) are distinct, wherein the structures encompassed by formula (vi)-(ix) cannot be derived based on the definitions of structural components of formula (ii)-(v). 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 Interpretation
In view of the above, it is noted that for the purposes of applying art the only formulas for substituent Z of Formula (I) being considered are those corresponding to formulas (i)-(v); as detailed above the formulas of Z corresponding to formulas (vi)-(xi) structurally redefine the group and are structurally distinct from formulas (i)-(v), such that they do not fall within the scope of independent claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1, 3-5, 7, 9, 14, 19-20, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over US 2013/0052130 A1 (previously cited on PTO-892; herein after referred to as "Davis") and WO 2017/089894 A1 (previously cited on PTO-892; herein after referred to as "Kim").
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With regard to claims 1, 3, and 24, Davis teaches general and "substantially pure" branched discrete polyethylene glycol (dPEG) constructs useful in attaching to a variety of biologically active groups, for example, preferential locators, as well as biologics like enzymes, for use in diagnostics, e.g. imaging, therapeutics, theranostics, and moieties specific for other applications (Abstract). Two exemplary alternating lysine-containing dPEG4 units are described, one of includes Fmoc-NH-dPEG4-(Lys)-dPEG4-(Lys)-dPEG4-(Lys)-dPEG4-(Lys)-OH (Page 238), which is shown below.
It is specifically noted, that the structure above reads on a polymer of instant Formula I wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 can both be divalent ethylene, X is NH, Z is -AA-H (i.e., the side chain of Lysine), x = 1, and s = 4. While it is noted that the dPEG4-(Lys) groups of the structure above are alternating, it is noted that Davis suggests that a linear arrangement of such groups (i.e., dPEG-active amino acid) can have a continuous arrangement as demonstrated by a similar exemplary dPEG-active amino acid composition utilizing tyrosine, shown below, wherein the terminal NH group of Tyr is covalently connected to the C=O that attaches the dPEG units.
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As such, from the exemplary structures of Davis, one of ordinary skill in the art would recognize that a polymeric structure comprising instant Formula I is suggested by Davis. It is further noted that Davis teaches that in one final product form of the invention, a chemically reactive moiety can be directly or indirectly attached to a biologically active group-that is, a group that performs a desired function/interaction in vivo, whether as a preferential locator (i.e., a targeting agent; e.g., an antibody or antibody fragment), a nanoparticle, an enzyme, or other substance (Paragraph 0021); wherein a chemically reactable group includes a group that is reactive or can be made reactive, such as a chemically reactive moiety or a chemically reactive moiety with a protective group (Paragraph 0022). “Preferential locator” often can be used largely interchangeably with ligand or "targeting group"; with respect to neoplastic tissue (cancer cells), a "preferential locator" (or "locator") specifically binds a marker produced by or associated with, for example, neoplastic tissue, antibodies and somatostatin congeners being representative such locators wherein, broadly, a "locator" includes a substance that preferentially concentrates at the tumor sites by binding with a marker (the cancer cell or a product of the cancer cell, for example) produced by or associated with neoplastic tissue or neoplasms (Paragraph 0088). As disclosed by Table 2 on Page 19, and as would be recognized by one having ordinary skill in the art, maleimide is an acceptable reactive moiety that can be utilized in the dPEG-containing constructs of Davis (see, for example, Page 206-207), wherein the maleimide may be covalently
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bound to either the Lysine side chain or any available, reactive amine group (shown below).
The maleimide can then be used to covalently attach an antibody to constructs of the invention (i.e., maleimide covalently binds to an active agent and covalently binds to the polymeric structures of the invention, meeting the limitation of a polymer-antibody linker required by instant claim 1) and/or each maleimide may conjugate two different active moieties (e.g., two different monoclonal antibody Fab’ fragments; exemplary antibody targets prostate-specific membrane antigen (PSMA) upregulated in prostate cancer) (see Example 5, Pages 238-239).
However, it is noted that while Davis suggests the use of linkers in constructs of the invention (see Paragraph 0047), the exemplary constructs most closely related to the instant invention do not explicitly demonstrate the use of a linker to attach a biologically active agent (i.e., L1 required to attach B as required by instant claim 1 wherein Z is of formula (ii)). This deficiency is remedied by Kim.
Kim teaches antibody-drug conjugates comprising an antibody, a linker, and at least two active agents wherein the linker comprises a peptide sequence of a plurality of amino acids where at least two active agents are covalently coupled to the side chains of the amino acids (Abstract). At least two of the active agents may be coupled to the side chains of lysine (Page 2). Each active agent can be independently selected from chemotherapeutic agents and toxins (Page 11). In some embodiments, the active agents may be coupled to the side chains of amino acids through one or more linkers (i.e., secondary linkers, meeting the limitation of linking group L1 of instant claim 1) (Page 39), wherein exemplary secondary linkers are provided on Page 40 and read on instant formulas (ii) and (iv)-(v) of claim 1.
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed that the invention of Davis could be modified by the teachings of Kim. The invention of Davis reads on antibody-drug conjugates comprising a dPEG-reactive amino acid polymer (exemplary polymer shown below):
wherein the lysine repeats may be contiguous instead of alternating (as taught by Davis), which reads on the instantly claimed continuous repeats of instant Formula I, wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 can both be divalent ethylene, X is NH, x = 1, s = 4, Z is of formula (i), the side chain of the reactive amino acid (i.e., -AA-) is Lysine and can be linked directly to a biologically active agent B (e.g., an antibody, enzyme, nanoparticle, etc., as suggested by Davis), and wherein reactive amines may be used to attach maleimide groups that are covalently bound to the polymer and an antibody (i.e., is a polymer-antibody linker). One of ordinary skull in the art would recognize that such a polymer may be modified based on the teachings of Kim such that biological agent B may be a drug (e.g., chemotherapeutic agent or toxin) wherein such drugs may be attached with a secondary linker (i.e., as represented by a Z group of formulas (ii), (iv), and (v)). It would have been obvious to combine the teachings of Davis and Kim to arrive at the instantly claimed antibody-drug conjugate structure because both Davis and Kim teach antibody-drug constructs, wherein Davis teaches dPEG-reactive amino acid polymers as the foundation for such conjugates wherein the dPEG constructs have increasing serum half-lives as the size and MW increase (Davis Paragraph 0009) and Davis suggests the attachment of antibodies and other active agents, wherein one of ordinary skill in the art would recognize that the active agents could be, in addition to those of Davis, chemotherapeutic agents and/or toxins which can be attached to reactive amino acid side chains with or without a secondary linker, as taught by Kim, wherein the resultant conjugate would reasonably be expected to be functional (i.e., therapeutic by way of biologically active antibodies, enzymes, nanoparticles, therapeutic agents) and targetable via an antibody.
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With regard to claim 4, it is noted that the biologically active agents of both Davis and Kim are attached via the reactive amino group of the Lysine side chain such that the biologically active agent (i.e., B) is covalently bound to -AA- through the N heteroatom of the Lysine side chain, either directly or via a secondary linking group. For example, Davis provides exemplary embodiments wherein the Lysine side chain is reacted to add a maleimide group for conjugation of an antibody (see, for example, Pages 206-207):
and Kim further provides and exemplary embodiment wherein biologically active agents (B) are attached via the Lysine side chain (see, for example, Page 44):
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Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
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With regard to claim 5, it is noted that the antibody-drug conjugate of claim 1 rendered obvious by Davis and Kim comprises a polymer-antibody linker that is derived from maleimide, and wherein the maleimide may be covalently attached to the N of the NR group of instant Formula (I), as demonstrated by the exemplary structure provided at Pages 206-207:
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 7 and 9, as provided above, the structure rendered obvious by Davis and Kim reads on the antibody-drug conjugate of instant claim 1 wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 can both be divalent ethylene, X is NH, x = 1, and s = 4, Z is of formula (i), the side chain of the reactive amino acid (i.e., -AA-) is Lysine and can be linked directly to a biologically active agent B (e.g., an antibody, enzyme, nanoparticle, etc., as suggested by Davis), and wherein reactive amines may be used to attach maleimide groups that are covalently bound to the polymer and an antibody (i.e., is a polymer-antibody linker) and such a polymer may be modified based on the teachings of Kim such that biological agent B may be a drug (e.g., chemotherapeutic agent or toxin) wherein such drugs may be attached with a secondary linker (i.e., as represented by a Z group of formulas (ii), (iv), and (v)). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 14, Kim further teaches that each active agent may be independently selected from (i.e., may be the same or different) wherein exemplary active agents are provided on Pages 11-13; said active agents include small molecule drugs (e.g., SN-38), peptides, proteins, oligonucleotides, etc. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 19, as provided above, the structure rendered obvious by Davis and Kim reads on the antibody-drug conjugate of instant claim 1 wherein Y is C=O, Q is T1O(CH2CH2O)sT2 wherein T1 and T2 can both be divalent ethylene, X is NH, x = 1, and s = 4, Z is of formula (i), the side chain of the reactive amino acid (i.e., -AA-) is Lysine and can be linked directly to a biologically active agent B (e.g., an antibody, enzyme, nanoparticle, etc., as suggested by Davis), and wherein reactive amines may be used to attach maleimide groups that are covalently bound to the polymer and an antibody (i.e., is a polymer-antibody linker) and such a polymer may be modified based on the teachings of Kim such that biological agent B may be a drug (e.g., chemotherapeutic agent or toxin) wherein such drugs may be attached with a secondary linker (i.e., as represented by a Z group of formulas (ii), (iv), and (v)). Furthermore, an exemplary branched embodiment comprising polymer repeats corresponding to instant formula I is shown below (see Page 224):
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It is noted that the linear portion of such a structure (i.e., linear repeat of instant Formula (I); boxed in the reproduced structure above) corresponds to instant Formula (III), wherein and antibody is covalently bound to the polymer via the NH group of instant Formula (I) via maleimide (i.e., polymer-antibody linker), R” corresponds to an -OH group, and z corresponds to an integer of 2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 20, Kim teaches antibody-drug conjugate pharmaceutical compositions comprising an antibody-drug conjugate and a pharmaceutically acceptable
Excipient (Page 20). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 25, it is noted that Davis discloses that biologically active groups that can be conjugated to the polymers of the invention are groups that perform a desired function/interaction in vivo, whether as a preferential locator (i.e., a targeting agent; e.g., an antibody or antibody fragment), a nanoparticle, an enzyme, or other substance (Paragraph 0021); wherein a chemically reactable group includes a group that is reactive or can be made reactive, such as a chemically reactive moiety or a chemically reactive moiety with a protective group (Paragraph 0022). “Preferential locator” often can be used largely interchangeably with ligand or "targeting group"; with respect to neoplastic tissue (cancer cells), a "preferential locator" (or "locator") specifically binds a marker produced by or associated with, for example, neoplastic tissue, antibodies and somatostatin congeners being representative such locators wherein, broadly, a "locator" includes a substance that preferentially concentrates at the tumor sites by binding with a marker (the cancer cell or a product of the cancer cell, for example) produced by or associated with neoplastic tissue or neoplasms (Paragraph 0088). Example 5 utilizes maleimide groups, wherein each maleimide may conjugate two different active moieties (e.g., two different monoclonal antibody Fab’ fragments) wherein the exemplary antibody of the example targets prostate-specific membrane antigen (PSMA), which is upregulated in prostate cancer (see Example 5, Pages 238-239). Additionally, Kim discloses various exemplary antibodies for conjugates of the invention wherein said antibodies are specific for an epitope or antigenic molecule, including epitopes/antigenic molecules associated with cancer; exemplary antibodies include, for example, anti-CD20 rituximab, anti-HER2 trastuzumab, and anti-EGFR cetuximab (see Pages 49-50). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
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.
Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-7, 9, 11, and 14-22 of copending Application No. 18/687,256 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
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Claim 1 of the reference application is drawn to an antibody-drug conjugate comprising: (i) an antibody or antigen-binding fragment thereof; (ii) a polymer comprising a repeat of Formula (II) or Formula (II’), both reproduced below, wherein the structural components are defined by the claim; and (iii) a polymer-antibody linker which is covalently bonded to both the antibody and the polymer.
It is specifically noted that from the structural definitions provided by claim 1: pS may be 0; QA may be a polymer -Y-Q-X- wherein Y is selected from C=O, C=NH, C=NRA and C=S, X is selected from O, NH, NRA and S, RA is C1-20 hydrocarbyl, and each Q is independently selected from -CH2(NMe(C=O)CH2)o-, -T1O(CH2CH2O)sT2- and -T1O(CH2CH2CH2O)sT2-, wherein T1 is selected from a divalent methylene, ethylene, propylene or butylene radical, T2 is selected from a divalent methylene, ethylene, propylene or butylene, o is an integer from 0 to 100, and s is an integer from 0 to 150; R is hydrogen or C1-20 hydrocarbyl; x is an integer from 1 to 6; and Z is independently selected from, for example, formulas (i)-(v) reproduced below, wherein the structural components of formulas (i)-(v) are defined by claim 1.
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Thus, when pS = 0, QA is a polymer -Y-Q-X-, and Z is a group of formulas (i)-(v), it is noted that both Formula (II) and (II’) of the reference application read directly on instant claim 1 Formula (I). Reference application claim 3 further limits claim 1 wherein pS = 0. Claims 6-7 each further limit claim 1 wherein, respectively, (i) each QA is a polymer of -Y-Q-X- and (ii) each Z is independently selected from a group of formulas (i)-(v), or a group of formulas (xvi)-(xviii), or a group of formulas (xxiv)-(xxx). Claim 9 further limits claim 1 regarding, for example, Z of formulas (ii)-(v) as shown below:
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It is noted that reference application formulas (xxvi)-(xxix) read directly on instant claim 2 formulas (vi)-(ix). Claim 11 further limits claim 9, wherein:
(I) each QA’ is a polymer -Y'-Q'-X'-, optionally wherein:
(a) Q' is selected from -T1’O(CH2CH2O)s’T2'- and -T1’O(CH2CH2CH2O)s’T2'-, X' is selected from O, NH, NRA' and S, and Y' is selected from O, NH, NRA' and S: or
(b) Q' is -CH2(NMe(C=O)CH2)o'-, X' is selected from -(C=O)-O-, -(C=O)-NH-,- (C=O)-NRA'-, and -(C=O)-S, and Y' is selected from O, NH, NRA' and S; and/or
(II) R' is selected from hydrogen and C1-6 alkyl, preferably wherein R' is hydrogen, methyl, ethyl or n-propyl.
Claim 14 further limits claim 1 wherein the -AA- groups comprised within the Z groups are further limited to specific amino acid side chains (e.g., 2,3-diaminopropionic acid, lysine, etc.). Claim 15 further limits claim 1 wherein the polymer-antibody linker is derived from maleimide, monobromomaleimide, vinyl sulfones, bis(sulfone)s, allenamides, dehydroalanine, alkenes, perfluoroaromatic species, sulfone reagents that are Julia-Kocienski like, N- hydroxysuccinamide-ester activated carboxylate species, aldehydes, ketones,hydroxylamines, alkynes and azides. Claim 16 further limits claim 1 wherein: (a) X is O or NH and Y is C=O; and/or (b) X' is O or NH and Y' is O or NH; and/or (c) XS is O or NH and YS is C=O; and/or (d) XS’ is O or NH and YS’ is O or NH. Claim 17 further limits claim 1 wherein:
(a) Q is -CH2CH2O(CH2CH2O)sCH2CH2- or -CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-, preferably wherein s is from 1 to 100, more preferably wherein Q is
-CH2CH2O(CH2CH2O)sCH2CH2- and s is 3, 7, 11, 23 or 35; and/or
(b) Q' is -CH2CH2O(CH2CH2O)sCH2CH2- or -CH2CH2CH2O(CH2CH2O)sCH2CH2CH2-, preferably wherein s is from 1 to 100, more preferably wherein Q is
-CH2CH2O(CH2CH2O)sCH2CH2- and s is 3, 7, 11, 23 or 35.
Claim 18 further limits claim 1 wherein each biologically active moiety -B is the same or different, such that each B- H or B-OH is independently selected from small molecule drugs, peptides, proteins, peptide mimetics, antibodies, antigens, DNA, mRNA, small interfering RNA, small hairpin RNA, microRNA, PNA, foldamers, carbohydrates, carbohydrate derivatives, non- Lipinski molecules, synthetic peptides and synthetic oligonucleotides, preferably small molecule drugs. Claim 19 further limits claim 1, such that for each Z group of the recited formulas, the linker moieties (e.g., L1 of formula (ii)) are further defined. Claim 20 further limits claim 19 wherein Xl is NH, X2 is 0,X3 is 0, preferably wherein one of m and p is either 2 or 3, and the other is 0. Claim 21 further limits claim 1 such that the antibody-drug conjugate has a structure
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according to one of Formulas (III), (III’), (IV), or (IV’):
Claim 22 is drawn to a pharmaceutical composition comprising an antibody-drug conjugate according to claim 1 and a pharmaceutically acceptable excipient. Thus, the reference application, in view of the structural definitions provided in the claims, reads directly on instant claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25; specifically with regard to instant claims 24-25, it is noted that an antibody meets the instant limitation of a “targeting agent”.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-5, 7-9, 11, 13-20, 22, and 24-25 are pending. Claims 16-17 and 22 are withdrawn. Claims 1-5, 7-9, 11, 13-15, 18-20, and 24-25 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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