Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-20 are pending.
Claim 16 is withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-15 and 17-20, drawn to an immunoconjugate, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 61/762,563, filed February 8, 2013, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 9, 2025 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Rejection Withdrawn
The rejection of claims 3, 8-9, 11 and 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the claim amendment.
The enablement rejection of claims 1-15 and 17-20 is withdrawn in light of additional evidence that a skilled person can readily make and use the claimed immunoconjugates, see p. 12-16 of amendment filed December 9, 2025.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 5-15 and 19-20 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69).
Claim 1 encompasses any immunoconjugate comprising a modified antibody or antibody antigen binding fragment thereof and a payload drug moiety, wherein the modified antibody or antibody antigen binding fragment comprises a cysteine substitution at amino acid position 152 of a heavy chain constant region of the antibody or antibody antigen binding fragment, wherein the amino acid position is numbered according to the EU system, and wherein the immunoconjugate has a drug antibody ratio of 2, 4, 6 or 8.
Claim 2 encompasses the immunoconjugate of claim 1, further comprising one or more additional cysteine amino acid substitutions of the heavy chain constant region of the antibody or antibody antigen binding fragment.
Claim 3 encompasses the immunoconjugate of claim 1, further comprising a cysteine substitution at amino acid position 375 of the heavy chain constant region of the antibody or antibody antigen binding fragment, wherein the amino acid position is numbered according to the EU system.
Claim 4 encompasses the immunoconjugate of claim 1, wherein the drug antibody ratio is 2.
Claim 5 encompasses the immunoconjugate of claim 1, wherein the drug antibody ratio is 4.
Claim 6 encompasses the immunoconjugate of claim 1, wherein the drug antibody ratio is 6.
Claim 7 encompasses the immunoconjugate of claim 1, wherein the drug antibody ratio is 8.
Claim 8 encompasses the immunoconjugate of claim 1, wherein the payload is attached to the modified antibody or antibody antigen binding fragment indirectly or directly through a sulfur of the cysteine at amino acid position 152.
Claim 9 encompasses the immunoconjugate of claim 1, wherein the payload is attached to the modified antibody or antibody antigen binding fragment indirectly or directly through a linker.
Claim 10 encompasses the immunoconjugate of claim 9, wherein the linker is a cleavable linker, a non- cleavable linker, a thiol-maleimide linkage, a -S-CH2-C(=0)- linkage, or a disulfide linkage.
Claim 11 encompasses the immunoconjugate of claim 1, wherein the payload is a cytotoxic agent.
Claim 12 encompasses the immunoconjugate of claim 1, wherein the payload is selected from the group consisting of taxanes, DNA-alkylating agents, anthracyclines, tubulysin analogs, duocarmycin analogs, auristatin E, auristatin F, and maytansinoids.
Claim 13 encompasses the immunoconjugate of claim 1, wherein the antibody is an IgG antibody, a monoclonal antibody, a chimeric antibody, a humanized antibody, a fully humanized antibody, a bispecific antibody, or a multi-specific antibody.
Claim 14 encompasses the immunoconjugate of claim 1, wherein the antibody or antibody antigen binding fragment specifically binds to a cell surface marker characteristic of a tumor.
Claim 15 encompasses a composition comprising the immunoconjugate of claim 1.
Claim 17 encompasses any immunoconjugate comprising a modified antibody or antibody antigen binding fragment thereof and any drug moiety, wherein the modified antibody or antibody antigen binding fragment comprises a cysteine substitution at amino acid position 152 of the heavy chain constant region of the antibody or antibody antigen binding fragment, wherein the amino acid position is numbered according to the EU system, and wherein the immunoconjugate has a drug antibody ratio of 2.
Claim 18 encompasses any immunoconjugate comprising a modified antibody or antibody antigen binding fragment thereof wherein the modified antibody or antibody antigen binding fragment comprises a combination of cysteine substitutions at amino acid positions 152 and 375 of a heavy chain constant region of the antibody or antibody antigen binding fragment, wherein the amino acid positions are numbered according to the EU system, and wherein the immunoconjugate has a drug antibody ratio of 4.
Claim 19 encompasses any immunoconjugate comprising a modified antibody or antibody antigen binding fragment thereof wherein said modified antibody or antibody antigen binding fragment comprises a combination of cysteine substitutions at amino acid positions 152 and 375 of a heavy chain constant region of said antibody or antibody antigen binding fragment, wherein said amino acid positions are numbered according to the EU system, and wherein the immunoconjugate has a drug antibody ratio of 8.
Claim 20 encompasses the immunoconjugate of claim 19, further comprising one or more additional cysteine amino acid substitutions of the heavy chain constant region of the antibody or antibody antigen binding fragment.
The specification exemplifies preparation of trastuzumab Cys mutant antibodies, see Example 2.
The full length amino acid sequence of wild-type trastuzumab heavy chain is shown as SEQ ID NO: 1 and that of the light chain is SEQ ID NO: 90, see p. 130. The Trastuzumab IgG1 heavy chain comprises a cysteine substitution at amino acid position 152 (E152C) in the CH1 domain of the heavy chain constant region of the antibody comprises SEQ ID NO: 10; the Trastuzumab IgG1 heavy chain comprises a cysteine substitution at amino acid position 375 (S375C) in the CH3 domain and comprises the amino acid sequence of SEQ ID NO: 50, see Tables 1, 9, 14. The specification discloses conjugation of Cys mutant trastuzumab antibody with MC-MMAF, see Example 6, Table 17. The combination of Cys sites to produce drug conjugates with drug-to-antibody ratios greater than 2, see Example 10. Example 11 shows selection of Cys sites based on ADC hydrophobicity. Trastuzumab Pcl-MMAF ADCs varied greatly when the MMAF was attached different sites, see Figures 23, 25, p. 174.
However, there is no description of the genus of immunoconjugates that permit one of ordinary skill in the art to recognize the members of the genus which encompass any antibody or antigen binding fragment thereof and any drug moiety.
Even assuming the antibody or antigen binding fragment thereof binds specifically to HER2 in the immunoconjugates, the specification discloses just one trastuzumab antibody that binds to just human HER2 wherein the antibody is linked to just MMAF at HC-E152C (SEQ ID NO: 10) in the CH1 domain, HC-S375C (SEQ ID NO: 50) in the CH3 domain.
However, one species of anti-HER2 antibody or antigen binding fragment thereof conjugated to just MMAF at position 152C, or 152C and 375C is not representative of the genus.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Notably, there is no limitation on the structure or function of the antibody, or the epitope to which it binds and the structure of the drug moieties conjugated to the cysteine at position 152, or positions 152 and 375 in the heavy chain constant region of all antibodies or antigen binding fragment thereof conjugated to which drug which can be used to treat patient with which disease. Without such as description, one of ordinary skill in the art would be unable to distinguish which immunoconjugates would fall within the scope encompassed by the claims and which do not.
Regarding number of species of immunoconjugates, the specification does not disclose a representative number of species of such immunoconjugates comprising any antibody or antigen binding fragment thereof having a cysteine at position 152 or position 152 and 375 conjugated to any and all drug payload having a drug antibody ratio of 2, 4, 6 or 8, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function. One of skill in the art cannot visualize or recognize the members of the genus of the actual claimed immunoconjugate themselves having a drug ratio of 2, 4, 6 or 8.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., ( J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.) Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding antibody drug conjugate, the state of the prior art is such that the location or site of conjugation on the drug and the antibody affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Even assuming the antibody is trastuzumab conjugating to MMAF via a cysteine at position 152 in the heavy chain constant region, this does not produce a drug antibody ratio of 4, 6 or 8 (claims 1, 2, 6, 7, 19, 20) because each antibody comprises just two heavy chains and each heavy chain comprises one cysteine at position 152 in CH1 domain, resulting a drug antibody ratio of 2 (2 x 1 is 2).
Regarding claim 3, conjugating a drug to a cysteine at position 152 in the CH1 domain and a cysteine at position 375 in the CH3 domain still does not produce an immunoconjugate comprising a drug antibody ratio of 6 or 8 (claim 3, 6, 7, 19, 20). This is because each antibody comprises just two heavy chains and each heavy chain comprises one cysteine at position 152 in CH1 domain and one cysteine at position 375 in CH3 domain, resulting a drug antibody ratio of 4 (2 x 2 is 4). There are insufficient working examples. It is unpredictable which immunoconjugate comprising undisclosed antibody or antigen binding fragment thereof and drug is effective for treating which disease.
Although one of skill in the art could make a mAb against antigen, or screen a human antibody phage display library, test candidates, and produce a corresponding antibody immunoconjugate, note that: “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d, 2004 WL 260813, at 89 (Fed. Cir. Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features that are common to the genus. That is, the specification provides neither a representative number of species that encompass the genus nor does it provide a description of structural features that are common to genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number” of species. Since the disclosure fails to describe common attributes or characteristics that identify members of the genus of immunoconjugates, and because the genus is highly variant, the disclosure is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species of immunoconjugate to describe the genus as broadly claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must 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.’’ (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, only (1) an immunoconjugate comprising a modified trastuzumab antibody or antigen binding fragment thereof that binds to HER2 and a drug moiety, wherein the modified antibody or antigen binding fragment thereof comprises a cysteine substitution at position selected from the group consisting of position E152C, positions E152C and S375C, positions E152C, S375C and K334C; and E152C, S375C, K334C and K392C of a heavy chain constant region of the antibody or antigen binding fragment thereof, wherein all amino acid positions are number according to the EU system, wherein the drug moiety is auristatin MMAF or MMAE and wherein the immunoconjugate has a drug antibody ratio of 2, 4, 6 or 8, (2) the said immunoconjugate wherein the cysteine substitution is at positions E152C and S375C of the heavy chain constant region of the antibody, and wherein the immunoconjugate has a drug antibody ratio of 4, (3) the said immunoconjugate wherein the cysteine substitution is at positions E152C, S375C and K334C of the heavy chain constant region of the antibody, and wherein the immunoconjugate has a drug antibody ratio of 6, (4) the said immunoconjugate wherein the cysteine substitution is at positions E152C, S375C, K334C and K392C and wherein the immunoconjugate has a drug antibody ratio of 8 meet the written description requirement, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicant’s arguments filed December 9, 2025 have been fully considered but have not been found persuasive.
Applicant’s position is that [i]ndependent claims 1 and 17 are directed to, inter alia, immunoconjugates comprising a modified antibody or antigen binding fragment thereof and a drug moiety, wherein the modified antibody or antigen binding fragment comprises a cysteine substitution at amino acid position 152 of a heavy chain constant region of the antibody or antigen binding fragment. Independent claims 18 and 19 are directed to, inter alia, immunoconjugates comprising a modified antibody or antigen binding fragment thereof and a drug moiety, wherein the modified antibody or antigen binding fragment comprises a combination of cysteine substitutions at amino acid positions 152 and 375 of a heavy chain constant region of the antibody or antigen binding fragment.
The specification sufficiently describes a platform technology rather than an individual immunoconjugate
Applicant respectfully asserts that the presently claimed subject matter is not directed to a particular antibody sequence or drug moiety. Rather, the presently claimed subject matter relates to platform technology, specifically, the specific substitution(s) in a heavy chain constant region of a modified antibody or antigen binding fragment thereof that contributes to the desired conjugation efficiency and stability of immunoconjugates that contain such substitution(s). Importantly, as detailed below, the specification provides clear guidance to direct a skilled artisan from the disclosed examples to the full scope of the claimed subject matter. Requiring recitation of a particular antibody sequence or particular drug moiety in the independent claims would unduly narrow the scope of the claims.
The specification shows possession of the claimed genus, which encompasses various antibodies
Furthermore, the instant specification provides working Examples demonstrating that immunoconjugates comprising various antibodies can be produced. For instance, as acknowledged by the Office, the instant specification, e.g., at working Example 6, describes conjugation of MMAF with a modified trastuzumab antibody comprising a cysteine substitution at amino acid position 152 of the heavy chain constant region.6 Example 11 describes measurement of hydrophobicity of these immunoconjugates by hydrophobic interaction chromatography (HIC); as shown in Table 28, the DAR2 HIC retention time for HC-E152C-MMAF was 20.4 minutes. In addition, as detailed in working Example 8, an immunoconjugate was formed by conjugation of maleimide-MMAF with a modified trastuzumab antibody comprising a cysteine substitution at amino acid position 152 of the heavy chain constant region, and the immunoconjugate demonstrated an IC50 of 7.62E-05pM or 1.42E-04 pM, respectively, in cell proliferation assays with breast cancer cell lines.7
As described in the instant specification at page 148, lines 6-9, "[b]ecause constant regions of antibodies are highly conserved in primary sequence and structure, Cys mutant residues that are identified as good payload attachment sites in the context of trastuzumab will also serve as preferred attachment residues in other antibodies" (emphasis added). To demonstrate the transferability of these generic conjugation sites to other antibodies, Applicant cloned a set of cysteine mutations, including cysteine mutations at amino acid position 152 or 375, into antibody 14090, which binds to a different target protein than trastuzumab.8 As described in working Example 8 of the instant specification, the antibody 14090 Cys-MMAF immunoconjugates displayed antigen dependent cell killing in cell proliferation assays.9
Therefore, the specification as filed clearly provides sufficient support that multiple antibodies, including those that bind to different target antigens, can be modified through cysteine substitutions at amino acid position 152 or 375 of the heavy chain constant region to form immunoconjugates. The instant specification further teaches production of immunoconjugates with drug antibody ratios (DARs) greater than 2 through combinations of cysteine substitutions, e.g., at pages 174-178. For example, the instant specification at page 174, lines 30-31, provides that "[e]xamples of such combinations are antibodies featuring Cys mutant combinations of HC-E152C and HC-S375C" (emphasis added).
The specification also shows possession of the claimed genus, which encompasses different drug moieties at various antibody drug ratios.
With regard to the Office's assertion that "there is no description of the genus of immunoconjugates that permit one of ordinary skill in the art to recognize the members of the genus which encompass...any drug moiety,"10 Applicant respectfully disagrees and asserts that exemplary drug moieties are disclosed in the application as filed. For instance, the specification at page 108, lines 17-25 provides:
the immunoconjugates of the present invention comprise a drug moiety selected from a V- ATPase inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor, proteasome inhibitors, an inhibitor of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder, topoisomerase inhibitors, RNA synthesis inhibitors, kinesin inhibitors, inhibitors of protein-protein interactions, and a DHFR inhibitor.
Additional exemplary drug moieties are provided in the specification, e.g., at pages 108-109. Therefore, the present application provides a representative number of species to describe the recited drug moiety.
With regard to the Office's assertion that "[e]ven assuming the antibody is trastuzumab conjugating to MMAF via a cysteine at position 152 in the heavy chain constant region, this does not produce a drug antibody ratio of 4, 6 or 8 (claims 1, 2, 6, 7, 19, 20) because each antibody comprises just two heavy chains and each heavy chain comprises one cysteine at position 152 in CH1 domain, resulting a drug antibody ratio of 2 (2 x 1 is 2), Applicant respectfully disagrees. Claim 1 recites that "the modified antibody or antigen binding fragment comprises a cysteine substitution at amino acid position 152 of a heavy chain constant region of the antibody or antigen binding fragment" (emphasis added). Thus, the modified antibody or antigen binding fragment recited in claim 1 can comprise one or more cysteine substitutions at another amino acid position of the antibody or antigen binding fragment, in addition to a cysteine substitution at amino acid position 152. In fact, dependent claim 3 recites an immunoconjugate further comprising a cysteine substitution at amino acid position 375 of the heavy chain constant region of the antibody or antigen binding fragment.
For at least these reasons, claims 1 and 17-19, and their dependencies, comply with the written description requirement, and a skilled artisan would recognize that Applicant was in possession of the claimed subject matter in view of the instant specification. Reconsideration and withdrawal of the rejection under 35 U.S.C. §112(a), written description, is respectfully requested.
In response to the argument that working example discloses cysteine mutations at amino acid position 152 or 375 has been cloned into antibody 14090, which binds to a different target protein than trastuzumab, the specification does not describe the heavy and light chain variable region or the six CDRs or common structure share by members of the genus of antibody or antigen binding fragment that specifically binds to any cell surface marker characteristic of tumor (claim 14). The specification fails to disclose a correlation between structure and function. “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” See Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Further, “A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus.” See AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69.
In this case, the specification does not disclose a representative number of species of such immunoconjugates comprising any antibody, e.g., IgG antibody, monoclonal, chimeric, humanized, fully humanized, bispecific or multispecific antibody or antigen binding fragment thereof specifically binds to any cell surface marker characteristic of tumor having a cysteine at position 152 and/or 375 conjugated to any and all drug payload having a drug antibody ratio of 2, 4, 6 or 8, nor sufficient relevant identifying characteristics in the form of structure or functional characteristics coupled with a known or disclosed correlation between structure and function. One of skill in the art cannot visualize or recognize the members of the genus of the actual claimed immunoconjugate themselves having a drug ratio of 4, 6 or 8 that binds to any cell surface marker characteristic of tumor.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.) Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
In response to the argument that claim 1 recites that "the modified antibody or antigen binding fragment comprises a cysteine substitution at amino acid position 152 of a heavy chain constant region of the antibody or antigen binding fragment, and the modified antibody or antigen binding fragment recited in claim 1 can comprise one or more cysteine substitutions at another amino acid position of the antibody or antigen binding fragment to produce a drug antibody ratio of 4, 6 or 8, it is noted that claim 1 recites “a cysteine substitution at amino acid position 152 of a heavy chain constant region or antigen binding fragment”. Independent claim 1 does not recite one or more cysteine substitution as argued.
In response to the argument that claim 3 recites further comprising a cysteine substation at amino acid position 375 of the heavy chain constant region of the antibody or antigen binding fragment, it is noted that position 375 is located in the CH3 domain. However, antigen binding fragment, e.g., Fab, Fab2, scFv do not have Fc domain comprising CH2-CH3 domains. In other words, antigen binding fragment does not have amino acid position 375. As such, a cysteine substitution at position 152 of an antigen binding fragment cannot produce a drug antibody ratio of 4, 6 or 8. Further, a combination of cysteine substitutions at positions 152 and 375 cannot produce a drug antibody ratio of 6 or 8 (claim 19).
For these reasons, the rejection is maintained.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-15 and 17-20 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 7, 8 and 11 of U.S. Patent No. 12,171,839. Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims differ only in scope. The independent claims 1 and 17 are drawn to an immunoconjugate comprising a modified antibody or antigen binding fragment thereof and a drug moiety, wherein the modified antibody or antigen binding fragment comprises a cysteine at amino acid position 152 of a heavy chain constant region of the antibody or antigen binding fragment, wherein the amino acid is numbered according to the EU system, and wherein the immunoconjugate has a drug antibody ratio of 2, 4, 6 or 8 generically whereas the independent claims of the ‘839 patent are limited to the specific antibody or antigen binding fragment thereof that binds to human cKIT. The ‘839 patent also teaches HC-E152C-S375C, see FIGS. 7A-7C. Otherwise, claims 1, 4, 8, 9, 11, 14-15 and 17 are anticipated or rendered obvious by the issued claims.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641