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 .
Status of the Claims
Claims 1-46 were originally filed 25 June 2024 and the preliminary amendment filed 5 September 2024 has been entered. Claims 1-2, 6-8, 11-12, 14-16, 18-22, 26, 28-34, 40-41 and 47-50 are currently pending and under consideration.
Claim Interpretation
For the purposes of applying prior art, the claim scope has been interpreted as set forth below
per the guidance set forth in MPEP § 2111. If Applicant disputes any interpretation set forth below,
Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in
the subsequent response to the instant action. Applicant is advised that a specialized definition should
be properly supported and specifically identified (see, e.g., MPEP § 2111.01 (IV), describing how Applicant may act as their own lexicographer).
Claims 14 (line 3), 19 (line 7), 21 (line 6), and 29 (line 4) all recite “optionally”. Limitations recited in the clauses that follow “optionally” are not required limitations of the claim. For example, claim 14 is drawn to wherein the antibody molecule forms a heterodimer, “optionally” comprising particular substitutions in the first and second heavy chains. Claim 14 is understood as only requiring the antibody molecule to form a heterodimer and does not require the substitutions recited within the optionally clause.
Claim 29 is drawn to wherein the topoisomerase I inhibitor has a particular formula which comprises RL wherein RL is a linker for connection to the antibody molecule. The claim also sets forth “optional” linkers. Claim 29 is interpreted as not requiring the optional linkers set forth in (ia) and (ib).
Claim Objections
Claim 2, 6-8, 11, 12, 14-16, 18-22, 28-34, 40, 41, and 48-50 are objected to because of the following informalities:
Claims 2, 6-8, 11, 12, 14-16, 18-22, 28-34, 40, 41, and 48-50 recites, “The method of treatment” in line 1 and should recite, “The method of treating a cancer” for consistency.
Claims 28-30 and 32 recite structural formulas; however, some structures are read left to right while other structures are read right to left relative to either the drug or the antibody. For example, claim 29 formula I is understood as Antibody-Linker (i.e., RL)-Drug while formula (ia) is read as Drug-ia-Antibody. Claims should be amended to have consistent reading of structures relative to the antibody.
Appropriate correction is required.
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, 2, 6-8, 11, 12, 14-16, 18-22, 26, 28-34, 40, 41, and 47-49 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.
The specification while being enabling for:
A method of treating a cancer comprising administering an antibody drug conjugate comprising: a first antigen binding domain that binds epidermal growth factor receptor (EGFR); and a second antigen-binding domain that binds c-Met, wherein the first and second antigen binding domains comprise particular sets of CDR sequences and conjugated to SG3932 (see claim 2, 8, 33, and 47) wherein the cancer is non-small cell lung cancer (NSCLC) or squamous cell carcinoma of the head and neck (SCCHN or SQHN) (instant claim 50);
the specification does not provide a sufficient enabling description of “…a variant thereof in which one or two or three amino acids in one or more of the HCDR1, HCDR2, or HCDR3 are substituted with another amino acid;” or ““…a variant thereof in which one or two or three amino acids in one or more of the LCDR1, LCDR2, or LCDR3 are substituted with another amino acid” in an antibody molecule that binds either EGFR or c-MET (see claims 1 and 7), an antibody with “at least 70%, at least 80%, at least 90%, or at least 95% sequence identity” to a particular VH and VL sequence for either target (see instant claims 6 and 11), conjugated to any linker drug combination (see claims 28-32). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in the scope of the claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claims 1 and 47 are drawn to treating any cancer. Furthermore, claim 1 is drawn to administering a genus of bispecific EGFRxc-Met antibodies wherein the CDRs for the EGFR binding domain has been described. The language of claim 1 encompasses treating any cancer with a genus of antibodies wherein the EGFR binding domain comprises 6 variable CDRs and any EGFR binding domain. Similarly, claim 7 is a genus of antibodies wherein the EGFR and c-Met binding domains each comprise 6 variable CDRs. In both claims 1 and 7 the antibody comprises any framework regions. There is no evidence in the disclosure that antibodies with every combination possible presented in claims 1 and 7 were isolated nor are the any disclosed species to support claiming the genus of antibodies that bind to EGFR or c-MET with variable CDRs.
Claims 6 and 11 are drawn to wherein the antibody has variable framework regions in addition to variable CDRs. Similarly, claims 6 and 11 encompass a genus of antibodies with at least 70% sequence identity to a particular VH or VL sequence. To put another way the EGFR antibody molecule can have approximately 36 or 33 substitutions in the VH and VL sequences, respectively while the c-MET antibody molecule can have approximately 33 or 30 substitutions in the VH and VL sequences, respectively.
Claims 28-32 are drawn to various genera of linker drug combinations conjugated to the genera of bispecific antibodies of claim 1 in the method of treatment. Specifically, claim 28 encompasses administering an antibody drug conjugate wherein the antibody portion comprises the genus of antibodies set forth in claim 1 conjugated to the drug exatecan (see claim 28 formula A*) via any linker with any antibody drug ratio (DAR). Similarly, claim 29 is drawn to wherein the conjugated drug further comprises any linker. Claims 30 and 31 are drawn to wherein the antibody is conjugated to any linker drug combination and broadly a DAR of 2-8. Claim 32 is drawn to a linker drug combination comprising 1 of 2 linkers wherein additional aspects of the linker (i.e., Q and X) comprise additional variability. For example, X is drawn to a structure with at least one or more PEG repeats.
Regarding antibodies with variable CDRs
In the disclosure, the following antibodies RAA22/B09-57 and QD6/B09-57 were isolated and characterized (see specification pg. 82, 2nd paragraph). EGFR antibody RAA22 is a variant resulting from one positive mutation in HCDR3 from the parent H4 antibody and QD6 is a variant in four combined mutations in LCDR2, LCDR3, and HCDR3 (see specification pg. 82, 2nd paragraph). Applicant discloses bispecific antibodies with low affinity EGFR binding domains are more efficacious at treating cancer compared to conjugates comprising a higher affinity binding domain (see specification pg. 6 last para, Figure 12). Specifically, bispecific antibodies comprising the high affinity EGFR QD6 binding domain were not effective in treating the ST551 PDX model while the bispecific antibodies comprising the lower affinity RAA22 were effective (see specification figure 13 far right top and bottom). These experiments were done using full length antibodies conjugated with a specific linker drug combination (i.e., AZ1508) (see specification pg. 10, 2nd and 5th para). Indeed, Applicant shows bispecific antibodies with altered EGFR affinity have different mechanisms of internalization wherein the high affinity EGFR binding domain drives internalization while the low affinity EGFR binding domain require both arms to engage to drive internalization (see specification pg. 93, 2nd para). Therefore, the ordinary artisan would recognize the particular CDRs which determine antibody binding characteristics are important for determining both the safe and efficacy of the claimed bispecific antibody.
Applicant’s disclosure of two species of antibodies with variable CDRs represent the extent of antibodies the Applicant was in possession of at the time of filing (i.e., one amino acid substitution and 4 amino acid substitution for EGFR alone). The c-MET antibody B09-57 was selected as the most potent variant of 0021U3-B09; however, the number of substitutions required to achieve this variant is not disclosed (see specification pg. 81, 2nd paragraph). It is noted that the claim 1 recites the HCDRs 1-3 and LCDRs1-3 from the RAA22 EGFR antibody while claim 7 recites the HCDRs 1-3 and LCDRs1-3 from the B09-57 c-MET antibody while providing no variants thereof. The current claims encompass a large genus of antibodies with variable CDRs of which 1 or 2 species are disclosed in the specification. In this case, not only were the variants not taught in the instant disclosure, but there is also no indication of what the variants would potentially bind to or guarantee that the variants would bind to EGFR or c-MET let along treat a cancer.
The state of the art prior to the effective filing date of the claimed invention demonstrates that antibody functionality is dependent on the entire antibody structure, particularly the combination of the heavy chain and light chain CDRs (all 6 CDRs) and surrounding regions, not just portions of the isolated antibody. For example, Culang discloses CDRs are believed to account for the recognition of the antigen and while not every amino acid in the CDR may directly bind to the antigen the non-binding CDR residues are important for maintaining the structural conformations of the CDRs (see Culang et al. (2013) The structural basis of antibody-antigen recognition. Front. In Immun. 2013. Vol. 4, Article 302, pgs. 1-13, in particular, pg. 3, 1st col., 3rd paragraph, pg. 41st col. 1st paragraph). Furthermore, Culang discloses integration of six CDRs together, each with its own unique amino acid composition and contact preferences could be the evolutionary response that enables antibodies to recognize any surface patch on the antigen (see Culang pg. 6, 1st col.-2nd col. 1st paragraph). Therefore, a person of ordinary skill in the art at the time of the effective filing date would understand the residues within the CDR regions are integral to either directly interacting with the antigen or maintaining the structure of the region that binds to the antigen and amino acid substitution in the CDRs would affect one or both these attributes. As there is no disclosed or art-recognized correlation between structure and function, it would be impossible for one of ordinary skill in the art to predict which variations in each CDR and subsequent combinations would result in a structure that binds to EGFR or c-MET, particularly in view of claims 1 and 7 where each CDR sequence can have up to 3 amino acid substitutions.
Regarding antibodies conjugated to any linker drug combination
The specification teaches engineering ADCs that are both safe and effective is challenging. Specifically,
“[A]lthough the concept is simple, achieving the ideal combination of ADC properties has proven challenging, as reflected by the limited number of ADC’s that have been approved to date”, and
“[U]ltimately, the key challenge in developing an ADC is balancing its efficacy and safety” (see specification pg. 4).
In particular, ADCs targeting the claimed EGFR and c-Met have had limited success. At the time of filing there were 2 EGFR ADCs one of which was discontinued due to unfavorable safety issues. The other EGFR ADC (i.e., depatuxizumab mafodotin) in Phase III development for glioblastoma had limited efficacy at tolerated doses in alternative solid tumors (see specification pg. 4). The specification discloses bispecific antibodies to the claimed targets may overcome the challenges of the single target ADCs. Specifically,
“[T]he nature of bispecific antibodies allows for fine tuning of the interactions between each target to impact the overall properties of the molecule, which could produce an ADC with an acceptable therapeutic window. This concept has been tested for EGFR and c-MET in vitro, but investigators have yet to demonstrate proof of concept in vivo of an improvement in safety or efficacy compared to the EGFR and c-MET ADC” (see specification pg. 4).
Applicant has provided two art recognized linker drug combinations. The first is the low affinity EGFR bispecific antibody, RAA22/B09, conjugated to two AZ1508, a tubulysin, and the second is conjugation to SG3932 however a DAR is not disclosed (see specification pg. 94 bottom-pg. 95 bottom, pg. 111 bottom-pg. 112 bottom). The ordinary artisan would recognize that Applicant’s disclosure that ADCs to the claimed targets face several challenges and have had limited success. In addition, the conjugation to two art recognized linker drug combinations is also not representative of the breadth of conjugation to any linker drug combination.
For example, claim 29 is draw to optional linkers comprising PEG repeats of at least one or more (see claim 29, in particular X is b1 and b2). The state of the art teaches the number of PEG repeats effects efficacy of antibody drug conjugates. Specifically,
“Typically, the PEG is incorporated as a spacer between the drug and the point of antibody attachment, which effectively places the drug on the end of a PEG tether. We postulated that this tethered configuration could in fact have detrimental effects on pharmacokinetics, as it may project the drug moiety into the aqueous environment and thereby increase its potential for nonspecific hydrophobic interactions” (see Lyon et al. (2015) Reducing hydrophobicity of homogenous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol 33, 733–735, in particular pg. 734, 1st col. 2nd para) and
“These results confirmed that PEG configuration affected apparent hydrophobicity and that tethering the drug increased overall ADC hydrophobic character. ADC pharmacokinetics paralleled the trends in overall hydrophobicity, with faster clearance of cAC10-5 and slower clearance of cAC10-6 compared to the non-PEGylated cAC10-4. Hydrophobicity and plasma clearance also correlated with the hepatic uptake of these ADCs as assessed by IHC (Supplementary Fig. 6)” (see Lyon pg. 734, 2nd col 1st para).
The state of the art also teaches the criticality of the linker in efficacy of ADCs as well as the choice of antigen binding domain and payload. Specifically,
“The major hurdle is developing agents with a sufficient therapeutic window between the toxic dose and efficacious dose, and the ADC linker plays a central role in determining both thresholds” (see Knopp and Thurber (2019) Severing ties: quantifying the payload release from antibody drug conjugates. Cell Chemical Biology. Vol. 26, Iss. 12, pgs. 1631-1633, in particular, pg. 1631, 1st col, end of 1st para),
“Alternatively, ineffective linker cleavage (or antibody degradation for non-cleavable linkers) following cell entry can hinder delivery of cytotoxic payload to the site of action. The opposing effect of limiting systemic toxicity while maintaining efficient intracellular payload release remains a major challenge for this field, and optimal combinations of linker and payload are an active area of research to address this obstacle” (see Knopp and Thurber pg. 1631, para spanning cols 2-3),
“While choice of target antigens and pay loads is important, antibody-payload conjugation methods and linker chemistry are also crucial elements for producing successful ADCs. In particular, instability of the linker and heterogeneity of the product (i.e., broad distribution of DARs) often negatively impacts ADC efficacy and therapeutic window, which often leads to difficulty or limitation in the optimization for clinical application and eventual failure in clinical trials” (see Tsuchikama and An (2018) Antibody-drug conjugates: recent advances in conjugation and the linker chemistries. Protein Cell. 9(1): 33-46, in particular pg. 43 cols. 1-2), and
“it is important to identify ADC linkers with optimal linker stability for each combination of antigen, target tumor type, and payload” (see Tsuchikama and An pg. 35 para spanning cols. 1-2).
Therefore, the ordinary artisan would understand the choice of antigen binding domain, linker, and payload are all critical to the overall efficacy of an antibody drug conjugate and the particular combinations can have unpredictable outcomes (e.g., increased clearance). Applicant’s disclosure of two art recognized linker drug combinations is not representative or predictive of the breadth of the genus.
Regarding treatment of any cancer
Applicant’s specification teaches the claimed ADC (i.e., low EGFR affinity) requires both EGFR and c-Met engagement to be internalized (see specification pg. 101 last para). While EGFR is overexpressed on a myriad of cancers it remains a difficult target due to exacerbated toxicities from expression on normal tissue (see specification pg. 2 bottom of middle para). Despite overexpression of EGFR in particular cancers (e.g., colorectal cancer) response rates with monotherapy have been limited (see specification pg. 2 middle). Therefore, the ordinary artisan would understand that expression of the target alone is not sufficient to confer efficacy of the bispecific. c-MET is also expressed in normal tissue and c-MET inhibitors have had variable success (see specification sentences spanning pgs. 2-3). For example, crizotinib has been approved for NSCLC while onartuzumab and tivantinib lacked efficacy in Phase II clinical trials (see specification pg. 3, 2/3 down the page). The ordinary artisan would recognize the bispecific antibody will also bind to normal tissue (i.e., on-target, off tumor) rather than just the cancer (i.e., on-target, on tumor) depending on the antigen binding domains chosen and the target expression. Binding to normal tissue acts as a “sink” that impacts the efficacy of the bispecific. In the instant claims the antibody disclosed in claim 47 comprises a low affinity EGFR binding domain in order to mitigate the toxicities and “sink” of the bispecific antibody binding to normal tissue.
The state of the art teaches the low affinity EGFR binding domains can have reduced efficacy in EGFRhigh expressing cancers. Specifically,
“In the design of cMet x EGFR bsADC, a lower affinity for EGFR is often selected to mitigate systemic toxicity associated with broad expression of EGFR in normal tissues. However, such bsADC may be less effective against EGFRhigh-expressing tumor cells, which are commonly found in heterogeneous tumors.” (see Gong et al. 1048 A differentiated cMet x EGFR bispecific antibody-drug conjugate demonstrated broad antitumor activity and promising safety profile in preclinical models. Journal for ImmunoTherapy of Cancer. 2024; 12, in particular Background).
The state of the art also teaches targeting either EGFR or c-MET in every cancer is highly unpredictable. Specifically,
“In the case of c-Met inhibition, clinical trials have yielded little benefit to patients. The failure of clinical trials raises the common concern to many targeting approaches of whether the appropriate patient population was selected. Met inhibitors are designed to reduce phosphorylation of c-Met, and thus, reduce signaling and pathway activity. We would argue the selection criteria of tumor type, total protein expression, and gene amplification have not been shown to correlate to pathway activity. Trials that utilized c-Met mutation as an inclusion criterion have utilized a marker shown to correlate with pathway activity. Still, c-Met mutations are relatively rare, resulting in the vast majority of trials not utilizing an appropriate marker. Furthermore, to date no Met clinical trial used c-Met phosphorylation in the selection of patients for clinical trial participation, which we believe to be the most accurate biomarker” (see Hughes and Siemann (2018) Have clinical trials properly assessed c-Met inhibitors. Trends Cancer; 4(2):94-97, in particular pg. 3, 1st full para).
The claimed antibody (see claim 47) is advantageous because it favors binding to the cancer rather than normal tissue increasing therapeutic efficacy and limiting on-target off tumor toxicities. However, Sellmann and colleagues used T47D breast cancer (see instant claims 40 and 49) cell lines to mimic “normal tissue” in assessing a bispecific EGFR c-Met structure due to its negligible c-MET expression and low EGFR expression (see Sellmann et al. as cited on the IDS received 09/26/2026 (i.e., 7 pages total, in particular pg. 2 reference 11 (bottom)), in particular, pg. 25111, 1st col. 1st para). The state of the art also recognizes that known cMET EGFR bispecific antibodies have been discontinued after Phase I clinical trials due to significant toxicities (see Shim 2020 Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations. Biomolecules 2020, 10, 360, in particular pg. 6, 3rd para). Therefore, the ordinary artisan would recognize that in order to minimize on-target off-tumor toxicities bispecific EGFR c-MET antibodies have to be administered at lower doses which will affect the overall efficacy of the antibody. Furthermore, the state of the art teaches that therapies effective in NSCLC are not predictive of success in pancreatic cancer when targeting EGFR (see Faller and Burtness (2009) Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. Biologics: Targets & Therapy Vol 3 pgs. 419-428, in particular pg. 424, 2nd col. 2nd full para). This is due primarily to the larger size of antibodies, the dense tumor microenvironment in pancreatic cancer, and reduced activating mutations in EGFR in pancreatic cancer compared to NSCLC (see Faller and Burtness pg. 424, 2nd col. 1st and 2nd full para).
Conclusion
Accordingly, in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to develop antibodies that bind to EGFR or c-MET encompassing up to 18 amino acid substitutions across six CDRs in any position of the CDR (see claims 1 and 7), paired with any c-Met binding domain (see claims 1, 2, 6, 12, 14-16, 18-21, 26, and 28-34), to treat any cancer (see claims 1-2, 6-8, 11-12, 14-16, 18-22, 26, 28-34, 40-41 and 47-50) is left to those skilled in the art, the present claims and disclosure amounting to nothing more than an invitation to the skilled artisan to invent such variants. Given the resource-intensive nature of the required experimentation, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily, and improperly, extensive and undue.
It is noted instant claim 50 is enabled.
Claims 1, 2, 6-8, 11, 12, 14-16, 18-21, 26, 28-34, 40, and 41, 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.
Regarding claims 1 and 7 are drawn to antibody molecules that bind either EGFR or c-MET reciting 3 specific heavy complementarity determining regions (HCDRs) and light complementarity determining regions (LCDRs) or variants including up to three amino acid substitutions in each of the 3 HCDRs and LCDRs for each target.
Claims 28-32 are drawn to various genera of linker drug combinations conjugated to the genera of bispecific antibodies of claim 1 in the method of treatment. Specifically, claim 28 encompasses administering an antibody drug conjugate wherein the antibody portion comprises the genus of antibodies set forth in claim 1 conjugated to the drug exatecan (see claim 28 formula A*) via any linker with any antibody drug ratio (DAR). Similarly, claim 29 is drawn to wherein the conjugated drug further comprises any linker. Claims 30 and 31 are drawn to wherein the antibody is conjugated to any linker drug combination and broadly a DAR of 2-8. Claim 32 is drawn to a linker drug combination comprising 1 of 2 linkers wherein additional aspects of the linker (i.e., Q and X) comprise additional variability. For example, X is drawn to a structure with at least one or more PEG repeats.
Based on the structure of claims 1 and 7, the antibodies as claimed can have up to 18 amino acid substitutions across the six CDRs for each target and still fall under the claim limitations creating a genus of antibodies that either i. bind EGFR comprising an antibody with 6 variable CDRs paired with any c-MET binding domain or ii. bind EGFR and c-MET comprising 6 variable CDRs for each binding domain. Furthermore, the structures can comprise any linker (see claims 28, 29, and 32) or any linker drug combination (see claim 30). There is no evidence in the disclosure that antibodies with every combination possible presented in claims 1 and 7 were isolated nor are there a substantial number of species disclosed to claim the genus of antibodies binding to EGFR or c-MET with variable CDRS that are claimed. In the disclosure, the following antibodies RAA22/B09-57 and QD6/B09-57 were isolated and characterized (see specification pg. 82, 2nd paragraph). EGFR antibody RAA22 is a variant resulting from one positive mutation in HCDR3 from the parent H4 antibody and QD6 is a variant in four combined mutations in LCDR2, LCDR3, and HCDR3 (see specification pg. 82, 2nd paragraph). In view of the disclosure the variations in CDRs represent the antibodies the applicant was in possession of at the time of filing (i.e., one amino acid substitution and 4 amino acid substitution for EGFR alone). The c-MET antibody B09-57 was selected as the most potent variant of 0021U3-B09; however, the number of variations required to achieve this variant is not disclosed (see specification pg. 81, 2nd paragraph). It is noted that the claim 1 recites the HCDRs 1-3 and LCDRs1-3 from the RAA22 EGFR antibody while claim 7 recites the HCDRs 1-3 and LCDRs1-3 from the B09-57 c-MET antibody while providing no variants thereof. The current claims would allow for many combinations of which none are disclosed. In this case, not only were the variants not taught in the instant disclosure, but there is also no indication of what the variants would potentially bind to or guarantee that the variants would bind to EGFR or c-MET. Furthermore, Applicant demonstrated two art recognized linker drug combinations were effective in treating PDX models of NSCLC (see specification pg. 102-104, example 8, figures 12 and 13, pg. 112, 2-3rd para, figure 17). There is no evidence from the disclosure that bispecific EGFR c-MET antibodies conjugated to every drug and linker were made nor are there a representative number of disclosed species to claim the genus of linker drug combinations encompassed by the instant claim language.
The state of the art prior to the effective filing date of the claimed invention demonstrates that antibody functionality is dependent on the entire antibody structure, particularly the combination of the heavy chain and light chain CDRs (all 6 CDRs) and surrounding regions, not just portions of the isolated antibody. For example, Culang et al. discloses CDRs are believed to account for the recognition of the antigen and while not every amino acid in the CDR may directly bind to the antigen the non-binding CDR residues are important for maintaining the structural conformations of the CDRs (see Culang et al. The structural basis of antibody-antigen recognition. Front. Immunol., 08 October 2013. Sec. B Cell Biology. Volume 4 – 2013. pg. 3, 1st col., 3rd paragraph, pg. 41st col. 1st paragraph). Furthermore, Culang et al. discloses integration of six CDRs together, each with its own unique amino acid composition and contact preferences could be the evolutionary response that enables antibodies to recognize any surface patch on the antigen (see Culang et al. pg. 6, 1st col.-2nd col. 1st paragraph). Therefore, a person of ordinary skill in the art at the time of the effective filing date would understand the residues within the CDR regions are integral to either directly interacting with the antigen or maintaining the structure of the region that binds to the antigen and amino acid substitution in the CDRs would affect one or both these attributes. As there is no disclosed or art-recognized correlation between structure and function, it would be impossible for one of ordinary skill in the art to predict which CDR combinations would result in a structure that binds to EGFR or c-MET, particularly in view of claims 24 and 25 where each CDR sequence can have up to 3 amino acid substitutions.
Furthermore, the state of the art teaches individual combinations of antigen binding domains, linkers and drugs have to tested. Specifically,
“While choice of target antigens and pay loads is important, antibody-payload conjugation methods and linker chemistry are also crucial elements for producing successful ADCs. In particular, instability of the linker and heterogeneity of the product (i.e., broad distribution of DARs) often negatively impacts ADC efficacy and therapeutic window, which often leads to difficulty or limitation in the optimization for clinical application and eventual failure in clinical trials” (see Tsuchikama and An pg. 43 cols. 1-2),
“it is important to identify ADC linkers with optimal linker stability for each combination of antigen, target tumor type, and payload” (see Tsuchikama and An pg. 35 para spanning cols. 1-2),
“Typically, the PEG is incorporated as a spacer between the drug and the point of antibody attachment, which effectively places the drug on the end of a PEG tether. We postulated that this tethered configuration could in fact have detrimental effects on pharmacokinetics, as it may project the drug moiety into the aqueous environment and thereby increase its potential for nonspecific hydrophobic interactions” (see Lyon et al. pg. 734, 1st col. 2nd para), and
“These results confirmed that PEG configuration affected apparent hydrophobicity and that tethering the drug increased overall ADC hydrophobic character. ADC pharmacokinetics paralleled the trends in overall hydrophobicity, with faster clearance of cAC10-5 and slower clearance of cAC10-6 compared to the non-PEGylated cAC10-4. Hydrophobicity and plasma clearance also correlated with the hepatic uptake of these ADCs as assessed by IHC (Supplementary Fig. 6)” (see Lyon pg. 734, 2nd col 1st para).
As there is no disclosed or art-recognized correlation between the antigen binding domain and particular linker drug combinations, it would be impossible for one of ordinary skill in the art to predict which linker drug combinations result in a structure that binds to the claimed targets, internalizes into the cell, and releases the cytotoxic payload in an amount effect to treat any cancer given the wide spread expression of both targets on normal tissue cells (i.e., sink, toxicities) and complex linker/payload chemistry (e.g., clearance, cleavable/non-cleavable, solubility, aggregation, mode of action).
The antibodies discussed above, with RAA22/B09-57 and QD6/B09-57, represent the antibodies that Applicant was in possession of at the time of filing. AZ1508 and SG3932 are the two linker drug combinations that Applicant was in possession of at the time of filing. It is not evident from the specification that every CDR combination possible in claims 1 and 7 would result in an antibody or binding fragment that binds to EGFR or c-MET nor does the disclosure demonstrate that applicant was in possession of each and every CDR combination possible at the time of filing. Additionally, it is not evident from the specification that every linker combination with the disclosed payloads would result in an ADC that effectively treats cancer nor was Applicant in possession of such combinations let alone any linker with any alternative drug combination. Overall, based on the disclosure, and the state of the art at the time of filing, a skilled artesian would not have recognized that applicant was in possession of the claimed invention at the time of filing.
It is noted claim 47-50 overcome the written description rejection.
Claim Rejections - 35 USC § 112
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 12-16, 18-20, 28-30, 32, 33, 40, 41, 47, 49, and 50 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 12 is drawn to first and second heavy and light chains wherein the chains comprise their respective VH or VL sequence and CH or CL region or a fragment thereof. The scope of the fragment thereof is unclear. For example, does the first heavy chain comprise a VH or a fragment thereof and a CH or a fragment thereof, or alternatively, does the first heavy chain comprise a VH and either a CH region or a fragment thereof. To put another way is claim 12 meant to encompass fragments of either VH or VL regions or only fragments of the claimed CH or CL domains.
In addition claim 12 is drawn to a “first heavy chain constant (CH) region”. It is unclear if the abbreviation CH is attributed to a full length constant region, or alternatively, the first domain of an antibody constant region (i.e., CH1). The claim recites a first heavy chain with no abbreviation which implies CH is in reference to the art recognized CH1 region; however, the claim also recites “a second heavy chain constant (CH) region” which implies CH is drawn to a constant region generically as a whole. The ambiguity likewise applies to claim 15, 16, 18, 19, 20 wherein the CH abbreviation is used throughout.
Claim 15 is drawn to modifications in the CH and CL regions. The scope of the claim is unclear. The antibody molecule comprises a modified CH and corresponding CL region wherein the substitution is a native non-cysteine to cysteine. This encompasses two embodiments. Specifically, a modified first CH paired with a modified first CL (i.e., corresponding) or a modified second CH pair with a modified second CL (i.e., corresponding). However, the wherein clause specifies these two embodiments. Therefore, it is unclear if the wherein clause is meant to further limit these embodiments or alternatively is a duplicate of parts a and b. The recitation of “can form a disulphide bond” does not require a disulphide bond.
Claim 28 is drawn to wherein the conjugate of claim 26 comprises a drug with the formula set forth in A*. The scope of the attachment is unclear. Claim 26 is drawn to administering a conjugate comprising the antibody molecule according to claim 1 conjugated to a drug. To put another way claim 26 is drawn to administering a conjugate comprising the antibody molecule of claim 1 attached to a drug. Therefore, it is unclear if the site of attachment disclosed in A* (see claim 28) is directly to the antibody as suggested by claim 26 (i.e., antibody molecule conjugated/attached to a drug), or alternatively, the point of attachment disclosed in A* meant to encompass intervening structures between the drug and antibody.
Claim 29 is drawn to wherein the topoisomerase I inhibitor has one formula; however, claim 29 depends from claim 28 wherein the topoisomerase I inhibitor has a different formula. It is unclear how the topoisomerase I inhibitor can have two different formulas.
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In addition, the scope of Q is unclear. For example, claim 29 recites Q and QX and also wherein Q is an amino acid residue, a dipeptide residue, a tripeptide or a tetrapeptide; however, X is a structure with PEG. As an example, it is unclear how Q in (ia) is a dipeptide residue (i.e., QX is such that Q) while X encompasses additional structures. To put another way it is unclear how Q can be one thing (e.g., a dipeptide residue) and also be more than dipeptide residue (e.g., also has a, b1, b2, c1, c2, and d).
Claim 29 is also drawn to parentheticals (see “X is” clause). It is unclear if what is recited in the paratheses is a limitation or alternatively an alternative to the preceding clause.
The scope of “Ia” (see second structure in claim 29) and “Ib” (see 5th structure in claim 29) is unclear. For example, Ia follows recitation of “I” which comprises a topoisomerase I inhibitor. It is unclear how “Ia” can comprise a structure less than “I”. The claim also recites “(ia)” and “(ib)” while also labeling the corresponding structures “Ia” and “Ib”. It is unclear these are meant to reference the same physical structures, or alternatively, “(ia)” and “(ib)” are meant to delineate parts of the overall claim structure (e.g., claim 29 part (ia) vs claim 29 part (ib)).
Claim 30 is drawn to a “formula IV” and also recites “(IV)”. It is unclear if “(IV)” is an abbreviation for “formula IV” or alternatively a separate entity.
Claim 32 is drawn to wherein the DL (i.e., drug having a linker) is a topoisomerase I inhibitor having a linker that is of formula III. The structure set forth in formula III also comprises a drug. Therefore the scope of the structure is unclear. Is claim 32 drawn to Antibody-Formula III-Drug, or alternatively, Antibody-Formula III wherein Formula III comprises both the drug and the linker. Similar issues as set forth for claim 29 are applicable to claim 32 as claim 32 refers to claim 29 for definitions of variables.
Claim 33 and 47 is drawn to the particular structure the antibody is conjugated to. It is unclear if what is recited in the parathesis is a limitation, or alternatively, a name for the structure.
Regarding claims 40, 41, 49, and 50 the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 1-2, 6-8, 11-12, 14-16, 18-22, 26, 28-34, 40-41 and 47-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-14, 26 and 27 of U.S. Patent No. 12,065,496 B2 (referred to herein as ‘496 patent) in view of Sellmann (see Sellmann et al. as cited on the IDS received 09/26/2026 (i.e., 7 pages total, in particular pg. 2 reference 11 (bottom)).
The ‘496 patent discloses an antibody drug conjugate comprising identical CDRs (see instant claims 1, 2, 7, 8, and 47) conjugated to an identical linker drug combination (see instant claims 26, 28-33 and 47) with a DAR of 6 (see ‘496 patent claims 26 and 27; see instant claims 30, 31, and 48). In addition, the ‘496 patent claims an antibody molecule with identical CDRs, VH, VL, heavy chain constant regions, light chain constant regions, and particular substitutions (see ‘496 patent claims 1-8, 10-14; see instant claims 1, 2, 6-8, 11, 12, 14, -16, 18-22).
Sellmann discloses bispecific EGFR c-Met ADCs (e.g., vc-MMAE) were effective in killing a NSCLC cell line (i.e., A549) (see Sellmann pg. 25112, 2nd col. last para, figure 4, Table 5, pg. 25114, 1st col. 2nd para). Specifically Sellmann discloses,
“Recently, several bsAbs targeting c-MET and EGFR have been developed that demonstrated synergistic effects regarding inhibition of tumor proliferation and metastasis” (see Sellmann pg. 25106, 2nd col. last para) and
“The appropriate balance between high selectivity and suitable potency in EGFR c-MET bispecific ADCs could potentially broaden the therapeutic window” (see Sellmann pg. 25114, 2nd col. 2nd para).
Therefore the ordinary artisan would substitute the bispecific EGFR c-MET ADC administered in a method of treating NSCLC as taught by Sellmann with the bispecific EGFR c-MET ADC claimed in the ‘496 patent. There is a reasonable expectation of success given Sellmann discloses an existing therapeutic window for bispecific ADCs.
Claims 1, 2, 6-8, 11, 12, 14-16, 18-22, 26, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 20, 22, 23, 24, 26, 27, 32, 33, 39, 41, 42 of copending Application No. 18/721647 (referred to herein as ‘647 application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘647 application claims a compound comprising an EGFR antigen binding domain with identical CDRs, VH and VL sequences are disclosed in instant claims 1, 2, and 6 (see ‘647 application claims 1 and 20) and a c-Met binding domain. In addition the ‘647 application claims the antibody conjugated to a drug (see ‘647 application claims 12 and 39). The ‘647 application also claims identical CDRS, VH, VL regions for the c-Met binding domain (see ‘647 application claims 22 and 23), modifications and substitutions in the constant region (see ‘647 application 24, 26, 27, 32, and 33), a pharmaceutical composition comprising the same (see ‘647 application claim 41), and a method of treating cancer comprising administering the claimed agent (see ‘647 application claim 42). This is pertinent to instant claims 1, 2, 6-8, 11, 12, 14-16, 18-22, 26, and 34.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 6-8, 11, 12, 14-16, 18-22, 26, 34, 40, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 20, 22, 23, 24, 26, 27, 32, 33, 39, 41, 42 of copending Application No. 18/721647 (referred to herein as ‘647 application) in view of Sellmann (see Sellmann et al. as cited on the IDS received 09/26/2026 (i.e., 7 pages total, in particular pg. 2 reference 11 (bottom)). Although the claims at issue are not identical, they are not patentably distinct from each other.
The reasons claims 1 and 26 are anticipated by the ‘647 application are set forth above.
The teachings of Sellmann are set forth above.
A person of ordinary skill in the art would specifically treat NSCLC as taught by Sellmann in a method of treating cancer as claimed by the ‘647 application given NSCLC cell lines are effectively eliminating using EGFR c-Met bispecific ADCs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1, 2, 6-8, 11, 26, 28-34, 40, 41, 47, 49, and 50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 108, 110-114, 124 of copending Application No. 18/360,542 (referred to herein as ‘542 application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The ‘542 application claims a method of treating cancer comprising and antibody drug conjugate comprising the following:
an identical EGFR and c-MET binding domain CDRs (see Seq ID Nos: 117-121 and 122-127; see ‘542 application claims 108 and 110),
identical VH and VL sequences (see Seq ID Nos: 128, 130, 132, and 134; see ‘542 application claim 111),
identical linker (see ‘542 application claim 112),
topoisomerase inhibitor (see ‘542 application claims 113 and 114), and
specific cancer (e.g., NSCLC) (see ‘542 application claim 124).
This is pertinent to instant claims 1, 2, 6-8, 11, 26, 28-34, 40, 41, 47, 49, and 50.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim allowed.
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/H.A.P./Examiner, Art Unit 1644 /AMY E JUEDES/Primary Examiner, Art Unit 1644
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