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 Objections
Claim 8 is objected to because of the following informalities: “platinum-resistant” in lines 2-3 should be amended to “platinum chemotherapy-resistant”. While platinum-resistant is understood to mean platinum chemotherapy-resistant, this amendment should be made to provide clarity that “the platinum chemotherapy” in line 3 of claim 10, which depends from claim 8, can refer to either the chemotherapy to which the subject is resistant or for the subject is ineligible.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 39 and 41 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and an abstract idea without significantly more. The claims recite a method of identifying a subject having HNSCC that is suitable for treatment with ficlatuzumab and cetuximab comprising assessing whether the HNSCC is HPV-positive or negative and wherein the subject is HPV-negative. The claims are directed to a natural phenomenon where HPS-negative disease responds favorably to the combination regimen and HPS-positive HNSCC does not. The claims are directed to an abstract idea or a mental process because the method requires only a single step – assessing – the is a mental step which can be completed entirely in the mind. This judicial exception is not integrated into a practical application because while the preamble mentions a treatment regimen, no step of treating is required. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed method only requires the single mental step. While claim 41 recites the means by which HPV status is determined, this is not an active step in the method and the claim recites it as merely optional.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 8, 10, 21, 22, 24, 28, and 36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “thereby treating the HNSCC that is HPV negative.”; see lines 6-7. It is unclear whether this limitation merely recites the inherent outcome of administering cetuximab and ficlatuzumab to a subject having recurrent/metastatic HPV-negative HNSCC or if the limitation intends to claim only instances where the method of administering results in successfully “treating the HNSCC that is HPV negative.” In other words, is one infringing if they administer cetuximab and ficlatuzumab to a subject having recurrent/metastatic HPV-negative HNSCC and it does not result in at least one of: (a) slowing tumor growth, (b) halting tumor growth, ( c) promoting tumor regression or disappearance, ( d) ameliorating a symptom of the cancer, ( e) curing the cancer, or (f) prolonging survival of the subject; see paragraph 0074? For the purpose of compact prosecution, the thereby clause is interpreted as reciting an inherent outcome of administering cetuximab and ficlatuzumab to a subject having recurrent/metastatic HPV-negative HNSCC.
Claims 3, 8, 10, 21, 22, 24, 28, and 36 are rejected for depending from claim 1 and failing to remedy the indefiniteness of claim 1.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 69 and 97 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.
Claim 69 recites a method of administering genera of antibodies which bind to HGF or EGFR and comprise an amino acid sequence at least 80% identical to the amino acid sequence of the recited SEQ ID NOs; see claims 69 (a)(ii), (a)(iii), (b)(ii), and (b)(iii). Claim 97 recites the composition comprising the anti-HGF and anti-EGFR antibodies of claim 69 and a carrier. These claims are directed partial structures with up to 20% variability anywhere within the structure and still retain the ability to bind HGF or EGFR. More specifically, the recited SEQ ID NOs are associated with the anti-HGF antibody, ficlatuzumab (SEQ ID NOs: 7 and 8, and 17 and 18), and the anti-EGFR antibody, cetuximab (SEQ ID NOs: 15 and 16, and 19 and 20).
The instant Specification teaches two anti-HGF antibodies (ficlatuzumab and rilotumumab) and eight anti-EGFR antibodies (cetuximab, imgatuzumab, necitumumab, amivantamab, zalutumumab, panitumumab, nimotuzumab, and matuzumab). However, these are not at least 80% identical variants of the recited SEQ ID NOs. For example, the alignment below shows the shared identity between SEQ ID NO: 7, the heavy chain variable region of ficlatuzumab in the QY line, and SEQ ID NO: 27, the heavy chain variable region of rilotumumab in the Db line. The similarity between the two anti-HGF antibodies described is well below 80% identical.
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Conversely, the alignment below shows the shared identity between SEQ ID NO: 17, the heavy chain of ficlatuzumab in the QY line, and SEQ ID NO: 31, the heavy chain variable region of imgatuzumab in the Db line. Despite sharing 85.1% identity, the two heavy chains belong to antibodies having different target antigens.
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The instant Specification does not provide any actual reduction to practice of any variants of anti-HGF or anti-EGFR antibodies having at least 80% identity to SEQ ID NOs: 7 and 8, 17 and 18, 15 and 16, and 19 and 20. There is no teaching in the Specification regarding which 20% of the structure can be varied while retaining the ability to bind HGF or EGFR. There is no information about which amino acids can vary from the recited SEQ ID NOs in the claimed genera of antibodies and still retain the ability to bind HGF and EGFR. Further, given the below 80% identity shared between SEQ ID NOs: 7 and 27, heavy chain variable regions of two antibodies taught by the Specification to both bind to HGF and the above 80% identity shared between SEQ ID NOs: 17 and 31, two heavy chains, one of anti-HGF antibody and one of an anti-EGFR antibody, one of ordinary skill in the art could predict which 20% of amino acids in the recited SEQ ID NOs can vary and still retain the ability to bind HGF or EGFR. The level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which of those proteins having at least 80% identity to SEQ ID NOs: 7 and 8, 17 and 18, 15 and 16, and 19 and 20 and have the ability to bind to HGF or EGFR. Based on the lack of knowledge and
predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genera of proteins based on disclosure.
Claims 69 and 97 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:
An anti-HGF antibody comprising a heavy chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 8, wherein the heavy chain variable region comprises the CDRs of SEQ ID NOs: 1, 2, and 3, and the light chain variable region comprises the CDRs of SEQ ID NOs: 4, 5, and 6;
An anti-HGF antibody comprising a heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 18, wherein the heavy chain comprises the CDRs of SEQ ID NOs: 1, 2, and 3, and the light chain comprises the CDRs of SEQ ID NOs: 4, 5, and 6;
An anti-EGFR antibody comprising a heavy chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 15 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 16, wherein the heavy chain variable region comprises the CDRs of SEQ ID NOs: 9, 10, and 11, and the light chain variable region comprises the CDRs of SEQ ID NOs: 12, 13, and 14; or
An anti-EGFR antibody comprising a heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 20, wherein the heavy chain comprises the CDRs of SEQ ID NOs: 9, 10, and 11, and the light chain comprises the CDRs of SEQ ID NOs: 12, 13, and 14;
does not reasonably provide enablement for:
An anti-HGF antibody comprising a heavy chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 8;
An anti-HGF antibody comprising a heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 17 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 18;
An anti-EGFR antibody comprising a heavy chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 15 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 16; or
An anti-EGFR antibody comprising a heavy chain comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO: 20;
Wherein the 20% variability can occur anywhere throughout the SEQ ID NOs.
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 or use the invention commensurate in scope with these claims.
Claim 69 recites heavy and light chain variable regions or heavy and light chains “comprising an amino acid sequence having at least 80% identity to the amino acid sequence of” the recited SEQ ID NOs; see claim 69 (a)(ii), (a)(iii), (b)(ii), and (b)(iii).
First, it is noted that the claim recites “an amino acid sequence” which could read upon a subsequence. However, the claim requires it have at least 80% identity to “the amino acid sequence” of the recited SEQ ID NOs. This reference to “the amino acid sequence” is understood to require at least 80% identity over the length of the recited SEQ ID NOs. In other words, while “an amino acid sequence” may refer to a subsequence, for example a truncation where 20% of the recited SEQ ID NO sequence is absent, it cannot refer to a five amino acid long subsequence where four of the five amino acid residues of the subsequence are identical to that found within the recited SEQ ID NO.
The primary issue with claim 69 is that while up to 20% of the heavy and light chain variable regions or heavy and light chains may differ from the recited SEQ ID NOs, there is no requirement that the CDRs remain unchanged.
It is well 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. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (PNAS. 79: 1979-1983; Published: March 15, 1982). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
MacCallum et al. (Journal of Molecular Biology. 262(5): 732-745; Published: October 11, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations; see page 733 right column and page 735 left column.
De Pascalis et al. (The Journal of Immunology. 169(6): 3076-3084; Published: September 15, 2002) demonstrated that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site; see page 3079 right column. Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs; see page 3080 left column.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (BBRC 2003, 307(1): 198-205; Published: July 18, 2003), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs. Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3; see page 199 left column and page 202 left column.
Chen et al. (Journal of Molecular Biology. 293: 865-881; Published: November 5, 1999) describes high affinity variant antibodies binding to VEGF wherein the results show that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3; see page 8660.
Similarly, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Murphy et al. (Journal of Immunological Methods. 463: 127-133; Published: October 12, 2018). Murphy et al. teaches that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystinleucine-arginine (MC-LR) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone; see page 130, Section 3.2, paragraph 2 and page 131, column 1, paragraph 2. The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR.
While the level of ordinary skill in the art is high, the level of unpredictability in the art is also high. In particular, it is unpredictable which amino acid residues within the CDRs can be modified and retain binding affinity.
The instant Specification teaches two anti-HGF antibodies (ficlatuzumab and rilotumumab) and eight anti-EGFR antibodies (cetuximab, imgatuzumab, necitumumab, amivantamab, zalutumumab, panitumumab, nimotuzumab, and matuzumab). However, the instant Specification does not teach variants having up to 20% variation from the recited SEQ ID NOs and retaining the ability to bind HGF or EGFR. And, more specifically, the Specification does not teach variants comprising variation in the CDRs.
The amount of experimentation to required to identify variants commensurate with the scope of the claims having at least 80% identity to the recited SEQ ID NOs, wherein the up to 20% variation occurs throughout the sequence, including the CDRs, and which retain the ability to bind would be enormous. One would have to mutate the recited SEQ ID NOs and probe through trial and error to identify which mutants having at least 80% identity to the recited SEQ ID NOs retained the ability to bind to HGF or EGFR.
Considering the unpredictability, the high level of skill, and the amount of direction provided, it would take more than reasonable experimentation to make or use the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bauman et al. (Journal of Clinical Oncology. 39(15): Abstract 6015; Published: May 28, 2021).
Regarding claims 1, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, Bauman et al. (2021) teaches treating recurrent/metastatic HPV-negative HNSCC subjects by administering 20 mg/kg ficlatuzumab (anti-HGF antibody) with 500 mg/m2 cetuximab (anti-EGFR antibody) every 2 weeks; see Background and Methods. Regarding claim 8, Bauman et al. (2021) teaches treating recurrent/metastatic HPV-negative HNSCC subjects that are resistant or ineligible for platinum chemotherapy or anti-PD-1 immunotherapy; see Methods.
Thus, Bauman et al. (2021) as evidenced by Agarkhed et al. and Tuna et al. anticipates claims 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96.
Claims 65, 76, 77, 89, 91, 92, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bauman et al. (Journal of Clinical Oncology. 35(15): Abstract 6038; Published: May 30, 2017).
Regarding claims 65, 76, 77, 89, 91, 92, and 96, Bauman et al. (2017) teaches treating recurrent/metastatic HNSCC subjects by administering 10 mg/kg or 20 mg/kg ficlatuzumab (anti-HGF antibody) with 500 mg/m2 cetuximab (anti-EGFR antibody) every 2 weeks; see Background and Methods.
Thus, Bauman et al. (2017) anticipates claims 65, 76, 77, 89, 91, 92, and 96.
Claims 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020).
Regarding claims 1, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, Bauman et al. (June 2020) teaches treating recurrent/metastatic HPV-negative HNSCC subjects by administering 10 mg/kg ficlatuzumab (anti-HGF antibody) with 500 mg/m2 cetuximab (anti-EGFR antibody) every 2 weeks or 10, 15, or 20 mg/kg ficlatuzumab (anti-HGF antibody) with 500 mg/m2 cetuximab (anti-EGFR antibody) every 2 weeks; see Abstract, Table 1, and Figure 1. Regarding claim 3, HPV status was determined by p16 immunohistochemistry; see ‘4.1. Human Subjects Considerations’. Regarding claim 8, Bauman et al. (June 2020) teaches treating recurrent/metastatic HPV-negative HNSCC subjects that are resistant or ineligible for platinum chemotherapy or anti-PD-1 immunotherapy; see Methods. Regarding claim 21, all subjects treated except 1 had a primary sites in the oral cavity, the pharynx, or the larynx; see Table 1.
Thus, Bauman et al. (June 2020) anticipates claims 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96.
Claims 65, 76, 77, 89, 91, 92, and 96 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bauman et al. (Journal of Clinical Oncology. 38(15): Abstract TPS6594; Published: May 25, 2020).
Regarding claims 65, 76, 77, 89, 91, 92, and 96, Bauman et al. (May 2020) teaches treating recurrent/metastatic HNSCC subjects by administering 20 mg/kg ficlatuzumab (anti-HGF antibody) with 500 mg/m2 cetuximab (anti-EGFR antibody) every 2 weeks; see Background and Methods.
Thus, Bauman et al. (May 2020) anticipates claims 65, 76, 77, 89, 91, 92, and 96.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 69, 71, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Journal of Clinical Oncology. 39(15): Abstract 6015; Published: May 28, 2021) as applied to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of Agarkhed et al. (WO 2007/147001 A2; Published: December 21, 2007) and Tuna et al. (WO 2018/015448 A1; Published: January 25, 2018).
The teachings of Bauman et al. (May 2021) as related to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 69, 71, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Journal of Clinical Oncology. 35(15): Abstract 6038; Published: May 30, 2017) as applied to claim(s) 65, 76, 77, 89, 91, 92, and 96 above, and in view of Agarkhed et al. (WO 2007/147001 A2; Published: December 21, 2007) and Tuna et al. (WO 2018/015448 A1; Published: January 25, 2018).
The teachings of Bauman et al. (May 2017) as related to claim(s) 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 69, 71, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020) as applied to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of Agarkhed et al. (WO 2007/147001 A2; Published: December 21, 2007) and Tuna et al. (WO 2018/015448 A1; Published: January 25, 2018).
The teachings of Bauman et al. (June 2020) as related to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 69, 71, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Journal of Clinical Oncology. 38(15): Abstract TPS6594; Published: May 25, 2020) as applied to claim(s) 65, 76, 77, 89, 91, 92, and 96 above, and in view of Agarkhed et al. (WO 2007/147001 A2; Published: December 21, 2007) and Tuna et al. (WO 2018/015448 A1; Published: January 25, 2018).
The teachings of Bauman et al. (May 2020) as related to claim(s) 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
The following analysis applies to the four rejections above: Bauman et al. (May 2021), Bauman et al. (May 2017), Bauman et al. (June 2020), or Bauman et al. (May 2020) in view of Agarkhed et al. and Tuna et al.
Neither Bauman et al. (May 2021), Bauman et al. (May 2017), Bauman et al. (June 2020), nor Bauman et al. (May 2020) teach the sequence of ficlatuzumab nor cetuximab.
Regarding claims 69, 71, and 74, Agarkhed et al. teaches that the antibody cetuximab is a chimeric antibody comprising the heavy and light chains of SEQ ID NOs: 2 and 4 which are 100% identical to instant SEQ ID NOs: 19 and 20, respectively; see paragraphs 36 and 37.
Agarkhed et al. does not teach the sequence of ficlatuzumab.
Additionally, Tuna et al. teaches that humanized anti-HGF antibody ficlatuzumab comprises the heavy chain and light chain variable regions of SEQ ID NOs: 37 and 38 which are 100% identical to instant SEQ ID NOs: 7 and 8, respectively; see pages 4 and 61.
It would have been obvious to one of ordinary skill in art and one would have had a reasonable expectation of success to administer the chimeric anti-EGFR antibody cetuximab comprising the heavy and light chains of instant SEQ ID NOs: 19 and 20 as taught by Agarkhed et al. and the humanized anti-HGF antibody ficlatuzumab comprising the heavy chain and light chain variable regions of instant SEQ ID NOs: 7 and 8 for treating cancer because Bauman et al. (May 2021), Bauman et al. (May 2017), Bauman et al. (June 2020), or Bauman et al. (May 2020) teach administering ficlatuzumab with cetuximab for the treatment of HNSCC.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 10, 39, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Journal of Clinical Oncology. 39(15): Abstract 6015; Published: May 28, 2021) as applied to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT03422536 (ClinicalTrials.gov; Published: May 18, 2020).
The teachings of Bauman et al. (May 2021) as related to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 10, 39, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020) as applied to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT03422536 (ClinicalTrials.gov; Published: May 18, 2020).
The teachings of Bauman et al. (June 2020) as related to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claims 10, 39, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020) as applied to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT03422536 (ClinicalTrials.gov; Published: May 18, 2020).
The teachings of Bauman et al. (June 2020) as related to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
The following analysis applies to the four rejections above: Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) in view of the Clinical Trial Listing for NCT03422536 (ClinicalTrials.gov; Published: May 18, 2020).
While Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) each teach that the subjects treated were participants in the Clinical Trial NCT03422536, neither reference teaches that platinum chemotherapy-resistant patients are resistant to one of the agents in claim 10 nor the method of identifying suitable subjects based on HPV status; see last sentence of Bauman et al. (May 2021) or Bauman et al. (May 2020) and the Materials and Methods of Bauman et al. (June 2020).
Regarding claim 10, the Clinical Trial Listing for NCT03422536 teaches that the subjects who are platinum chemotherapy-resistant had disease progression following treatment with carboplatin or cisplatin for example; see inclusion criteria.
Regarding claim 39, the Clinical Trial Listing for NCT03422536 teaches that the subjects were assessed for HPV status. The inclusion criteria teaches that the eligibility requirements for subjects with oropharyngeal primary site or unknown primary site disease is a known tumoral HPV status or assessing whether the HNSCC is HPV-positive or HPV-negative based on p16 immunohistochemistry or HPV DNA. Regarding claim 41, the Clinical Trial Listing for NCT03422536 teaches that subjects were required have recurrent and/or metastatic disease; see Inclusion Criteria.
Given that Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) all teach that subjects treated were participants in the Clinical Trial NCT03422536 and the Clinical Trial Listing for NCT03422536 teaches subjects who are platinum chemotherapy-resistant had disease progression following treatment with carboplatin or cisplatin and that patients were identified as suitable for the combination regimen by assessing the HPV status of the HNSCC and deemed eligible if the subject had recurrent or metastatic disease, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to treat subjects who are platinum chemotherapy-resistant and had disease progression following treatment with carboplatin or cisplatin, and assess HPV status of the HNSCC and identify an eligible subject if he or she has recurrent or metastatic disease as taught by the associated Clinical Trial Listing.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Journal of Clinical Oncology. 39(15): Abstract 6015; Published: May 28, 2021) as applied to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT02277197 (ClinicalTrials.gov; Published: April 18, 2019) and Bauman et al. (Journal of Clinical Oncology. 35(15): Abstract 6038; Published: May 30, 2017).
The teachings of Bauman et al. (May 2021) as related to claim(s) 1, 8, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020) as applied to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT02277197 (ClinicalTrials.gov; Published: April 18, 2019) and Bauman et al. (Journal of Clinical Oncology. 35(15): Abstract 6038; Published: May 30, 2017).
The teachings of Bauman et al. (June 2020) as related to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al. (Cancers. 12: 1537; Published: June 11, 2020) as applied to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96 above, and in view of the Clinical Trial Listing for NCT02277197 (ClinicalTrials.gov; Published: April 18, 2019) and Bauman et al. (Journal of Clinical Oncology. 35(15): Abstract 6038; Published: May 30, 2017).
The teachings of Bauman et al. (June 2020) as related to claim(s) 1, 3, 8, 21, 22, 24, 28, 65, 76, 77, 89, 91, 92, and 96, from which these claims depend are given previously in this Office action and are fully incorporated here.
The following analysis applies to the four rejections above: Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) in view of the Clinical Trial Listing for NCT02277197 (ClinicalTrials.gov; Published: April 18, 2019).
Neither Bauman et al. (May 2021), Bauman et al. (June 2020), nor Bauman et al. (May 2020) teach whether ficlatuzumab and cetuximab were administered sequentially or simultaneously.
Regarding claim 36, the Clinical Trial Listing for NCT02277197 teaches that ficlatuzumab and cetuximab were administered sequentially – “Ficlatuzumab will be administered 30-60 minutes after the completion of the cetuximab infusion”; see ‘Detailed Description’.
Given that Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) teach treating subjects having HNSCC with ficlatuzumab and cetuximab and Clinical Trial Listing for NCT02277197 teaches treating subject having HNSCC with ficlatuzumab and cetuximab and that the two agents were administered sequentially, it would have been obvious to one of ordinary skill in the art to administer the combination regimen taught by Bauman et al. (May 2021), Bauman et al. (June 2020), or Bauman et al. (May 2020) sequentially. Further, because Bauman et al. (2017) reports that the dosing in Clinical Trial NCT02277197 was “well tolerated” with no dose-limiting toxicities, one would have had a reasonable expectation of success to administer the combination regimen of ficlatuzumab and cetuximab sequentially.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 65, 74-76, 77, 89, 91, 92, and 97 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (WO 2009/126834 A2; Published: October 15, 2009).
Regarding claim 65, Kim et al. teaches treating cancer, including head and neck cancer, comprising administering and inhibitor of HGF, including an anti-HGF antibody, and an inhibitor of EGF, including an anti-EGFR antibody; see Kim et al. claims 8, 10, 15-17, 19, and 20. Kim et al. demonstrates that the combination regimen of an anti-HGF antibody, TAK-701, and an anti-EGFR antibody, M225, significantly reduced tumor volume; see Figure 1. Regarding claims 74, 76, and 77, the anti-HGF antibody is a monoclonal antibody which is human or humanized and the anti-EGFR antibody is a monoclonal antibody that is cetuximab (chimeric) or panitumumab (human); see claims 9-17 and paragraph 0012. Regarding claim 75, the anti-HGF and anti-EGFR antibodies administered can include fragments such as single-chain antibodies (scFv), Fv, Fab, and F(ab’)2; see paragraph 0030.
Regarding claims 89, 91, and 92, Kim et al. teaches that the anti-HGF and anti-EGFR antibodies may be administered at a therapeutically effective dose of 0.1 to 30 mg/kg (3.47 – 1040.46 mg/m2, assuming a weight of 60 kg and height of 170 cm) and administered daily, biweekly, weekly, every other week, or monthly depending on half-life, for example; see paragraph 0039.
Regarding claim 97, claim 23 of Kim et al. teaches a composition or a kit comprising humanized anti-HGF antibody, L2G7, and one of the anti-EFGR antibodies, cetuximab or panitumumab. Paragraph 0035 teaches that antibodies are typically provided in a pharmaceutical formulation, i.e. in a physiologically acceptable carrier.
Given that Kim et al. teaches treating cancer comprising administering anti-HGF and anti-EGFR antibodies and demonstrates that such a combination regimen results in a significant reduction in tumor volume compared to monotherapy or control, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success. Given that Kim et al. teaches that chimeric anti-EGFR monoclonal antibody, cetuximab, is approved for the treatment of colon cancer and HNSCC, and that the human anti-EGFR monoclonal antibody, panitumumab, is approved for treatment of colon cancer (0012) , it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer chimeric cetuximab when treating either colon cancer or HNSCC. Further, given that Kim et al. teaches that the antibodies may be fragments and states that reduced immunogenicity and genetically engineered antibodies are preferred (see paragraph 0030), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to administer antibody fragments. One would been motivated to use antibody fragments for their greater tissue perfusion and potential for reduced immunogenicity.
Regarding the doses and time intervals, Kim et al. provides a range of doses and intervals states that dosing regimens will depend on the dose required to “alleviate or at least partially arrest the disease being treated” and the half-life of the agents used; see paragraph 0039. "In regards to the specific dosage and interval amounts recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see MPEP 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie dosage and intervals) optimization is obvious."
Finally, regarding the composition comprising the anti-HGF and anti-EGFR antibodies and a pharmaceutically acceptable carrier, given that Kim et al. teaches a composition or kit comprising the two agents and that pharmaceutical formulations comprise an acceptable carrier, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success and predictability to make a composition comprising the anti-HGF antibody, the anti-EGFR antibody, and a carrier.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Burtness et al. (Lancet Oncology. 14: e302-09; Published: July 2013) teaches that HPV-negative HNSCC overexpresses EGFR and the anti-EGFR antibody, cetuximab, administered as a single agent has less than a 15% response rate; see Abstract. Burtness et al. teaches that the relationship between MET expression and HPV status has not been described, although the prognostic value of MET
expression was statistically robust in two cohorts of patients with oral cavity SCC, an anatomic site characterized as being HPV-negative; see e304. Burtness et al. teaches that in HNSCC xenografts, dual inhibition of MET, the receptor for HGF, and EGFR arrested tumor growth and suggests that HGF-MET inhibition may be used to prevent or overcome resistance to anti-EGFR therapy in HNSCC and that horizontal blockade of MET and EGFR might be advantageous in patients who are cetuximab-naive and in those who have received prior treatment; see e305.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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