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 .
Claim Status
Claims 1-10 as filed on 28 January 2025 are pending and under examination.
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 1-10 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 1-8, and 10, the phrases "preferably", "more preferably", "further preferably" , and " most preferably" render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The claims are clearly to an antibody-drug conjugate (ADC) comprising an antibody that binds EGFR, a linker, and a cytotoxic agent. The linkers and cytotoxic agents listed in claims 1 are all recited as preferred making it unclear if the limitations are merely exemplary or required by the claim.
Claim 2 subpart 3 recites a feature of a heavy chain constant region that is human IgG, IgM, IgD, or IgA then recites the exemplary IgG 1, 2, 3, or 4, the presence of preferably renders the claim as indefinite as it is unclear if IgG 1, 2, 3, or 4 are required by claim 2 subpart 3 or merely exemplary IgG heavy chain constant regions.
Claim 3 requires the anti-EGFR antibody has at least 70% identity of the heavy or light variable regions of SEQ ID NO: 1 or 2, respectively or at least 70% identity of heavy or light chain constant region of SEQ ID NO: 3 or 4, respectively. The claim then recites the preferred embodiment of SEQ ID NO: 1-4 with no percent identity. The use of “preferably” in subparts 1-4 makes the claim undefined as it is unclear if the claim subparts require one of SEQ ID NO: 1-4 as exemplary or as a requirement of the claim.
Claims 4 and 10 recite EGFR mutation in the non-small cell lung cancer of the method. Claim 4 recites specific preferred mutations, this renders the claim indefinite as all limitations following preferred in claim 4 could be exemplary or limiting making the metes and bounds of claims unclear.
Claims 5 and 10 recite types of EGFR-TKI to select from including osimertinib then preferred EGFR-TKI osimertinib, it is then unclear if the claim is to any of the listed EGFR-TKI or requires osimertinib.
Claim 6 is to a combination of a first and second drug and preferably the drugs are separated from each other. The preferred embodiment renders the claim indefinite as it is unclear if the claim is to all combinations of the first and second drug or to only separated drugs.
Claim 7 specifies the PD-1/PD-L1 inhibitor is an anti-PD-1 or anti-PD-L1 antibody with preferred listed antibodies. It is unclear if the listed antibodies are exemplary or limiting rendering the claim indefinite.
Claim 8 specifies a range of weight ration of the first and second drug then states a preferred narrower range. It is unclear if claim 8 is the to broader range first recited or the preferred narrower range rendering the claim indefinite. Claim 9 depends from claims with this issue and do not correct it and therefore is also
For the purpose of examination the claims were read as not requiring any of the listed preferred limitations.
Regarding claims 5 and 10, the parenthetical “(preferably, bronchoalveolar carcinoma)” renders the claim indefinite as it is unclear if the limitation within the parenthetical is limiting or merely exemplary. For the purpose of examination the claim were read as not requiring bronchoalveolar carcinoma.
Claim 7 contains the trademark/trade names Keytruda and Opdivo. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an anti-PD-1 antibody and, accordingly, the identification/description is indefinite.
Regarding claim 7, the phrase "e.g." renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 1-10 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.
MPEP § 2163 states that 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, or it may be satisfied by the 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. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 1 is to a method of preventing or treating non-small cell lung cancer by administering an antibody-drug-conjugate (ADC) where the antibody binds EGFR. The claim defines the antibody that binds EGFR as comprising a heavy and light chain where the heavy chain CDR 1, 2, and 3 are SEQ ID NO: 5, 6, and 7, respectively, or mutants thereof and the light chain CDR 1, 2, and 3 are SEQ ID NO: 12, 13, and 14, respectively, or mutants thereof. The specification provides examples of mutants of amino acid sequences (paragraph 0182), but does not provide a limiting definition. This allows for unlimited changes to the CDR sequences so the claim encompasses any ADC that comprises and antibody that binds EGFR.
Claim 2 limits the framework region but does not further limit the CDR sequences of the antibody of claim 1.
Claim 3 limits the heavy chain to at least 70% identity of SEQ ID NO: 1 and the light chain to at least 70% identity of SEQ ID NO: 2. This claim depends from claim 1 which has no limitations on the CDRs and claim 3 has percent identity the CDRs of claim 3 are not defined.
Claims 4-10 provide no limitations for the sequences of EGFR binding antibodies of the claims.
Summary of Species Disclosed in the original specification
Applicant discloses one EGFR binding antibody that comprises heavy chain CDRs of SEQ ID NO: 5, 6, and 7; with light chain CDRs of SEQ ID NO: 12, 13, and 14. This antibody is called BA03 ([0208]-[0215]). This antibody is disclosed as an ADC used in a method of treating cancer (Example 2).
State of the Relevant Art
Epidermal growth factor receptor (EGFR) is a cell surface receptor of the epidermal growth factor family. It is a transmembrane glycoprotein consisting of 1186 amino acid residues with a molecule weight of 170 kD. It is a type I tyrosine kinase receptor and has tyrosine kinase activity. It is expressed in many epithelial tissues including skin and hair follicles. Abnormal expression of EGFR or activation due to receptor mutation can lead to carcinogenesis. Many solid tumors have been found to express high levels of EGFR. EGFR is a known target for tumor therapy using anti-EGFR antibodies (CN 103772504 A) [0004]-[0005]) (IDS).
It has been well established in the art that the formation of an intact antigen-binding site in a conventional antibody requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (PTO-892) (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule”, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). But while this overall structure is shared amongst antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure of each monoclonal antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). The epitope of an antibody does not provide structure or sequence information about the antibody that binds it.
Further, the skilled artisan has long recognized that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Brown et al., J. Immunol., 156(9):3285- 91 (1996) (PTO-892). Brown teaches that although a single amino acid change in CDR2 of heavy chain of a particular antibody was tolerated, the antibody lost binding upon introduction of two amino acid changes in the same region. Brown, p. 3290 and Tables 1 and 2. Table 1 of Brown shows that even a conservative substitution does not ensure that functionality of the antibody is retained. These older citations are supported my more recent discoveries of why these substitutions change antibody activity. Marvin et. al., Biochemistry, 42(23):7077-7083 (2003) (“Marvin” PTO-892) teaches that changes to the heavy and light chains altered binding affinity (Table 2) with changes to the CDR having large impacts but the changes with the largest impact were from residues in the CDR, but not from ones interfacing with the antigen ( Page 7081 in col 1 “Conclusions and Discussion” and Page 7082 in Figure 4).
This is confirmed by Chiu et al., Antibodies, 8(55):1-80. (2019) (“Chiu” PTO-892). Chiu teaches that the complementarity-determining regions (HCDRs 1-3 and LCDRs 1-3) determine antigen binding requiring specific sequences and orientation of those sequences to properly form tertiary structures that can recognize and bind antigens (Page 4 in 1.2.2 first and last paragraphs and Figure 3). Chiu teaches that antibody modeling with known LCDRs 1-3, HCDR1 and HCDR2 could not predict HCDR3. The field has shown repeatedly over decades that Structure-Based antibody engineering is unable to predict antibody sequences (Page 6 in 1.2.6, Pages 10-11 in Section 2 in particular second paragraph of page 11). Chiu notes the advancement in antibody engineering but notes it is still not possible to predict the point mutations that would improve affinity in both antibodies and multispecific molecules (Page 51 in lines 6-12).
In general, absent at least the conserved structure of the CDRs of the heavy chain and light chain of an antibody, the skilled artisan generally would not be able to visualize or otherwise predict an antibody with a particular set of functional properties would look like structurally. An epitope does not inform one of skill in the art of the structure of the antibody that binds it and a partial structure of mutated CDRs or variable heavy or light chains do not provide sufficient information for the CDRs of an antibody.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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.
The specification discloses one EGFR binding antibody.
The genus of EGFR binding antibodies as part of an ADC for use in a method of treatment is a large and variable genus. A single antibody is not representative of the genus as changes to the CDRs change the binding activity and each species of antibody would have a unique CDR combination. The disclosure of a set of CDRs of an antibody provides written description for that antibody and not additional antibodies with varying CDR sequences.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
As described above the structure in an antibody that provides its binding activity
is the set of 6 CDRs. As changes to the amino acids of the CDRs change its function, the CDRs of the disclosed antibodies do not disclose additional antibodies. The binding activity of an antibody does not provide structure to an antibody. The limitation of binding EGFR or a mutant of the receptor does not provide any structure to the CDRs that bind them. The activity of inhibiting the growth of cancer does not provide any limitation to the structure of the antibody for use in the method of the claims.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know which of the CDR combinations of the claims would meet the structural and functional requirements for use in the method of the claims. The applicant has not provided a representative number of species for all antibodies that bind EGFR or mutants of EGFR and functions as part of an ADC in the method of the claims. The functional structure of an antibody are its 6 CDRs that provide its binding activity based on the sequences of those CDRs, the CDRs of one antibody do not provide one of skill in the art with the functional CDRs of additional antibodies so the variability of the CDRs of the rejected claims mean there is no structure/function correlation, and the disclosed species do not provide written description for additional antibodies. The applicant has shown a single species of an antibody that binds EGFR and functions within the method of treating non-small lung cancer which provides written description only for a method of treating non-small lung cancer with the administration of an ADC comprising HCDR 1, 2, and 3 of SEQ ID NO: 5, 6, and 7; with LCDR 1, 2, and 3 of SEQ ID NO: 12, 13, and 14. Given the lack of shared structural properties that provide the claimed binding activity, the single species of ADC described in a method of treatment, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention of the claims that includes a method of treatment with the varying sequences of the CDRs of the ADC or methods of prevention..
This rejection could be overcome by limiting the claims to specific combinations
of six CDRs in a method of treating non-small lung cell cancer that applicant has shown written description for.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of non-small cell lung cancer using the EGFR binding ADC of HCDR 1, 2, and 3 of SEQ ID NO: 5, 6, and 7 with LCDR1, 2, and 3 of SEQ ID NO: 12, 13, and 14, does not reasonably provide enablement for the prevention of non-small lung cancer comprising the administration of an ADC that binds EGFR where the antibody sequence varies. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breadth of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Breadth of Claims
The claims are to a method of preventing or treating non-small cell lung cancer by administering an EGFR binding ADC where the EGFR binding antibody has varying CDR sequences.
Guidance/Working Examples
The applicant discloses a method of treating cancer with only one disclosed EGFR binding antibody in an ADC (Figures 4-5 and Examples 3-4). Applicant discloses one EGFR binding antibody that comprises heavy chain CDRs of SEQ ID NO: 5, 6, and 7; with light chain CDRs of SEQ ID NO: 12, 13, and 14. This antibody is called BA03 ([0208]-[0215]). The applicant has only shown 1 EGFR antibody that functions as an ADC in a method of treating cancer.
State of the Art/Predictability
The art teaches treatment of cancer with EGFR targeted immunotherapy (CN 103772504 A) [0004]-[0005]) (IDS). EGFR binding ADCs is known for therapeutic use in non-small lung cancer with mutations of EGFR and interplay between EGFR and extracellular matrix (ECM) are known drivers of cancer development and progression but these drivers were not fully understood at the time the application was filed. The art teaches the use of ADCs that bind EGFR for the treatment of cancer but does not provide a method of prevention for ADCs that bind EGFR (Hassanein et. al. Frontiers in Oncology. 11:1-20. (2021) (PTO-892) (Abstract, Conclusions, and Figure 1).
The nature of the invention is such that the composition of the instant claim
must have a therapeutic benefit and be able to prevent cancer from forming in a patient, much like a vaccine. The art teaches that a vaccine must be prophylactic (Stedman's Medical dictionary, 2012, page 11760, in col 1 bullets 9-10)(PTO-892). The specification does not provide any teachings of the prophylaxis of cancers, how to determine the individuals who will develop one or more of the cancers of the claims, nor how to effectively prevent said particular diseases before occurrence. Thus, one of skill in the art would not be able to use the composition of the invention as a preventing vaccine without undertaking to determine how to select for individuals who will develop the diseases before the said disease occurs in the individual. An effective therapeutic protocol for the treatment or prevention of the formation of any disease is subject to a number of factors, which enter the picture beyond simply the administration of the antibody claimed.
It was well known in the art that different antibodies to the same antigen can have different effects following binding of their target antigen. Chan and Carter, Nature Reviews Immunology, 2010; 10:301-316 (PTO-892), summarize these different effects in Figure 2. The five distinct mechanisms include ligand blockade, receptor blockade, receptor downregulation, depletion of cells expressing the target, and signaling induction. The first four mechanisms generally act to inhibit the activity of cells expressing the receptor (or ligand counter receptor). Antibodies that function via these mechanism may broadly be considered antagonist antibodies. Antibodies that induce signals (agonist antibodies), however, may induce either positive or negative signals, depending not only on the nature of the target, but also on other factors such as the developmental state of the cell expressing the target. Chan teaches the administration of antibodies in the treatment of patients with multiple diseases including cancer, but does not teach the use of antibodies as vaccines or prevention. The mechanism of antibodies as therapeutics are inhibition of pathways, antibody-dependent cellular cytotoxicity (ADCC), modulation of T cell function, , and sensitizing cells for chemotherapy (Table 1). The art teaches that it was quickly discovered that antibody therapies results in the development of human anti-chimeric antibodies that bind the therapeutic and limit its half-life and clinical effectiveness (page 305 in col 1 in par 1). As a method of prevention would rely on producing a persistent immune response against a disease before it has formed. An antibody for use in the prevention of cancer is not taught in the art as shown by Chan as antibodies were immediately shown to not persist in a human after administration.
As reviewed in Reichert & Valge-Archer Reichert & Valge-Archer, Nat. Rev. Drug Disc. 2007; 6:349-356 (PTO-892), antibodies can mediate an anti-tumor effect by several different mechanisms. E.g., page 350 "Modes of Action." An antibody conjugated to a cytotoxic agent (an antibody-drug conjugate, or “ADC”) kills the tumor cell by a direct effect, as do radiolabeled antibodies. Id., col. 3. However, such immunoconjugates generally require that the antibody used to deliver the toxin/radiolabel be internalized into the tumor cell; and internalization is a property that is not shared by all antibodies, even among antibodies to the same tumor antigen. Id. at page 351, 1st column. Antibodies can also mediate their effect in an “unmodified” form by activating the immune system, either via ADCC, CDC, or direct induction of apoptosis. Id. at "Immune system activation.” But as the review discusses, not all antibodies have these activities, and ADCC and CDC both depend on the antibody isotype as well as the epitope of the antigen bound. Thus, the skilled artisan understood that the particular epitope targeted by the antibody and the form of the antibody were also determinants of therapeutic activity or lack thereof, even for the same target antigen.
Conclusion
The art teaches that EGFR can be targeted with antibodies for treatment of cancer and the specification shows the embodiment of an ADC comprising an antibody of HCDR1, 2, and 3 of SEQ ID NO: 5, 6, and 7; with LCDR 1, 2, and 3 of SEQ ID NO: 12, 13, and 14 in cell culture. But the art does not teach the prevention of cancer using anti-EGFR antibodies and the application has not shown the administration of the ADC in the prevention of non-small cell lung cancer.
The specification does not provide any teachings of prevention or vaccination, or how to determine the individuals who will develop non-small lung cancer, nor how to effectively prevent the formation of said disease before occurrence. An effective protocol for prevention of non-small lung cancer requires more than simply the administration of the ADC of the claims.
Predicting whether an individual is at risk for developing a disease is a very
unpredictable art. Several factors play a role including, genetic makeup, environmental
factors, age, diet, etc. Therefore, given the unpredictability of prevention and the unpredictability and the broad scope of the claims, undue experimentation would be
required to use the claimed antibody as a method for preventing cancer.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He (WO 2018006785 A1) (PTO-892).
Regarding claims 1 and 4, He teaches the use of an ADC comprising an anti-EGFR antibody, a linker and a drug (abstract and page 1 in par 1-2). Claim 1 allows for mutation of all of the CDRs so He teaches the antibodies of the claims. He teaches a method of treating non-small lung cancer (page 6 in par 9-11). He teaches the cancer has an EGFR mutation including L861Q as required by claim 1 subpart 2 and listed as a preferred mutation in claim 4. He teaches the ADC comprises a cytotoxic drug (page 9 in par 3). Claim 1 only lists preferred cytotoxic agents which are non-limiting, but He does teach MMAF as part of the ADC (page 24 in last par). Claim 1 only lists preferred linkers which are no limiting so the ADC of He teaches the ADC of instant claims 1 and 4.
Regarding claim 2, He teaches the heavy chain constant region of IgG1-4 and human kappa light chain (page 1 in par 2).
Regarding claim 5, He teaches a non-small cell lung cancer cell of HCC827 that are resistant to AZD9291 treatment but do respond to the ADCs of the invention (Example 9 starting on page 19 in particular page 22 in par 1).
Claims 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu (WO 2016131409 A1) (PTO-892), as evidence by Foster et. al. Experimental Cell Research. 243:359-366. (1998) (PTO-892).
Instant SEQ ID NO: 1 matches SEQ ID NO: 1 of Hu, instant SEQ ID NO: 2 matches SEQ ID NO: 2 of Hu.
Regarding claim 1-4, Hu teaches the treatment of non-small cell carcinoma including lung cancer that over expresses EGFR using an ADC (page 8 in par 10). Hu teaches the ADC has Formula I which matches Formula I of the claims (page 8 in par 2). Hu teaches the treatment of cancer with abnormal expression of EGFR including from mutations of the receptor (page 2 in par 4). Hu teaches MMAE as the drug in the ADC (Figure 9).
Regarding claim 5, Hu teaches the treatment of cancer cell A549 (Figure 5) which is a lung adenocarcinoma, as evidenced by Foster (abstract).
Claims 1-2 and 5-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cao (US 20170340733 A) (PTO-892).
Regarding claims 1, 6, and 9, Cao teaches the treatment of a subject comprising EGFR TKI resistance ([0131]). Cao teaches a method of treating cancer comprising the administration of an inhibitor of PD-1 or PD-L1 and an inhibitor of EGFR ([0784]) where the treatment of non-small lung cancer comprises an EGFR inhibitor that is an antibody ([0802]). Cao teaches the antibodies of the invention can be conjugated to a drug including cytotoxic drugs ([0235]-[0237]). Cao teaches the use of linkers in ADCs (0562]).
Regarding claim 2, Cao teaches the antibodies include IgG1, 2, 3, or 4 heavy constant regions ([0026]).
Regarding claim 5, Cao teaches the treatment of NSCLC including squamous and adenocarcinoma ([0120]-[0121]).
Regarding claim 7, Cao teaches the PD-1 inhibitor is nivolumab ([0032] and claim 34).
Regarding claim 8, Cao teaches the administration of their combination therapy where doses of the two agents have the first higher than the second, the first lower than the second, or the same dose for both ([0174]) and further teaches Nivolumab having a dose of about 1 mg/kg to about 5 mg/kg ([0155]).
Regarding claim 10, the claim is to the method of claim 9 wherein the EGFR-TKI resistant non-small lung cancer has one or more selected of mutations listed, is resistant to one of the listed inhibitors, or is one of the types of listed non-small cell lung cancer. Cao teaches the treatment of NSCLC including squamous and adenocarcinoma ([0120]-[0121]) as required by claim 10 in the final subpart.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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