DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-2, 4-12, 14-19, 22-23, 25, 27, 29, 34-42, 44-49, 52-55, 57, 59, 91, 117, 140, and 149) as well as the species of the protein design of claim 25, where the Fd portion in a) and b) is fused at its N-terminus to an scFv, wherein the Fab binds subdomain IV of human Her2 and the scFv binds subdomain II of human Her2, wherein the Fc domains are SEQ ID NO. 133 and 137 and the full length chains in the protein are SEQ ID NO. 156, 6, and 26, in the reply filed on 10/10/2025 is acknowledged.
Claims 1-2, 4-12, 14-19, 22-23, 52-53, 55, 57, 59, 91, 117, 140-144, and 150-153 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/10/2025.
Claim Status
Claims 3, 13, 20-21, 24, 26, 28, 30-33, 43, 50-51, 56, 58, 60-90, 92-116, 118-139, and 145-148 are canceled.
Claims 1-2, 4-12, 14-19, 22-23, 52-53, 55, 57, 59, 91, 117, 140-144, and 150-153 are withdrawn.
Claims 25, 27, 29, 34-42, 44-49, 54, and 149 are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement (IDS) submitted on 10/28/2025 is being considered by the examiner. Any strikethrough it is owed to lack of date.
Claim Objections
Claim 25 is objected to because of the following informalities: Part (c) should recite to form two Fab moieties. Furthermore, to avoid confusion and improve readability, the final wherein clause should be the first wherein clause and each alternative wherein clause should be preceded by roman numerals to organize the options.
Claim 36 is objected to because each sequence formula within the parenthetical phrases is superfluous and should be deleted. This same objection is also made for claim 39.
Appropriate correction is required.
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 36, 39, 42, and 49 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 36 recites a sequence of any one of several sequence identifiers. This language gives the claim multiple interpretations as it could mean the full sequence identifier is required by the claim or alternatively, it could mean that just any subsequence of the identifier is sufficient and if so, it is not clear which subsequence to use. The presence of multiple structural interpretations renders the claim indefinite. The same rejection is made for claim 39.
Claim 42 recites mutations and follows each set of them with according to EU numbering. However, it is not clear if just the final mutation is EU numbering or if all are to be such. The presence of multiple interpretations renders the claim indefinite. The same rejection is made for claim 49.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
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.
Claim 54 is 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 proteins comprising antigen binding domains with six parental CDRs each, does not reasonably provide enablement for similar proteins in which any one antigen binding site contains fewer than all six parental CDRs or mutated CDRs. 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.
The breadth of the claim is, in part, the protein of claim 25 wherein a) comprises a sequence with at least 90% identity to SEQ ID NO. 156, b) comprises a sequence having at least 90% identity to SEQ ID NO. 6, and each light chain of c) comprises a sequence having at least 90% identity to SEQ ID NO. 26. Each sequence here contains CDRs and so these can be mutated.
The nature of the invention is a bispecific anti-Her2 antibody-based protein.
The level of skill of one skilled in this art is high.
Figures 2B and 2C exemplify species within the elected design of claim 25. The binding domains are a Fab or scFv and so all require six CDRs to bind antigen.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). 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 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine, human, or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the mutated antibodies of the instant claims as broadly as claimed, encompassing mutated CDRs.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. 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. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach 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 (Abstract).
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies comprising fewer than all six parental CDRs or comprising mutated versions thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Claims 47-49 and 54 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.
Instant claim 54 is drawn to a genus of antibodies defined by the epitope they bind and partial structure but without a full set of six parental CDRs in any binding domain owed to the percent identity recitations. When one goes to the instant specification to identify a representative number of species to define the recited genera with respect to antibodies with six CDRs that bind the recited epitopes (subdomain II or IV of human Her2, 0328) but at least 90% identity to the variable regions of SEQ ID Nos. 156, 6, and 26, they find only the highly related binding domains in the informal sequence listing beginning on page 115 and going to page 145 of the specification. It appears the same CDR sets are used for each binding domain and the only difference in the sequences there are peptide chain design. Thus, it seems Applicant only teaches the CDR sets of the protein with SEQ ID NO. 156, SEQ ID NO. 6, and SEQ ID NO. 26 to represent the genus of 90% identity thereto and thus to each CDR set therein. Even if the prior art or specification provides additional antibodies, the totality of known antibodies would not be representative of each entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
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 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. . A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have varied parental CDR sets with any mutation, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of any other multispecific antibodies that bind human Her2 at subdomains II and IV other than those with the single species of CDR set for each domain provided by Applicant in the protein comprising SEQ ID Nos. 156, 6, and 26. Therefore, since only a single species of CDR set for each epitope is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“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). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used and such should include a complete CDR set for each target.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. One species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since only a single species or only a few species of antibodies are taught within the claimed genera above, those that bind the recited epitopes with CDR sets of at least 90% identity to those of the protein of claim 54 xi, the claim clearly fails the written description requirement. A representative number of species has not been taught to describe these genera. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. 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. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach 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 (Abstract). Thus, while Applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite all parental CDRs of the species disclosed since it is these structures together that are required to bind the recited antigen.
With respect to all claims rejected above, they permit mutation of Fc regions. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The specification does not describe the structures for substitution variants other than the examples discussed therein to include effector function modifiers like LALA mutations (0267 and 0293), TfR-binding mutations (0275-0281), half-life extenders (0302), and heterodimerization promoting mutations (0289). The state of art is that there is no sufficient correlation between the structure of any given modifications and required function.
Farrington et al (US 2007/0148164A1, pub. date: 6/28/2007) discloses that Fc point mutations at different positions with different amino acid modifications, even at same positions with different amino acid modifications (for example K288D, K288E and K288M) affect FcRn binding differently (see Figure 7).
Thus, one skilled in art cannot predict the functions for the broadly claimed variants. The disclosed variants are not representative for the broadly claimed genus because based on the disclosure of one variant, one cannot predict a function of another variant. A skilled artisan cannot visualize or recognize the identity of the members of the genus that exhibit just any functional property.
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997). The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
Since variants beyond those disclosed but still encompassed have unpredictable functionalities, it cannot be said that Applicant has disclosed representative species of the large genera claimed. Any future Fc structure encompassed may or may not have utility, and if it does, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of Fc regions. Thus, for this reason, all claims rejected above fail the written description requirement.
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.
Claim(s) 25, 27, 29, 34-35, 37-39, 44, 46, and 149 are rejected under 35 U.S.C. 102a1 as being anticipated by Li (US2017/0291955, published 10/12/2017).
Li teaches anti-Her2 binding molecules such as bispecific anti-Her2 antibodies and drug conjugates (Abstract). Pharmaceutical formulations comprising the disclosed compositions are taught (Abstract). Figure 7A shows a design that matches the elected species claim 25 in which scFvs that binds domain IV of Her2 are connected by linkers to the VH region of the 39S antibody. The 39S antibody binds domain II of human Her2 (0056). The second antigen binding site (scFv) can be that of trastuzumab which binds domain IV of human Her2 (0013). Thus, Li clearly anticipates claims 25, 27, 29 and 34.
With respect to claim 35, Li teaches at 0029-0031 the linker shown between each scFv and the antibody of Figure 7A and states that the linker can have 1-30 residues (0031).
With respect to claim 37, there is a linker shown between the VH and VL of the scFv of Figure 7A. Li teaches at 0028 the sequence of this linker as SEQ ID NO. 19 which has a subsequence of any of those in claim 39. Thus, claims 38-39 are anticipated by Li.
With respect to claim 44, Li teaches their bispecific antibody has an Fc region (shown in Figure 7A also) and it can be a mutant (0242-0243) and the Fc modification can reduce ADCC of the bispecific antibody (0244). L234F is an example (0244).
With respect to claim 46, Li teaches at 0038-0039 a hinge links CH1 and Fc regions and this is shown in Figure 7A also.
With respect to claim 149, Li teaches at 0053 a pharmaceutical composition with their Her2 bispecific antibody and a pharmaceutically acceptable carrier.
Thus, Li clearly anticipates the claims above.
Claim Rejections - 35 USC § 103
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.
Claim(s) 25, 27, 29, 34-39, 44-49, and 149 are rejected under 35 U.S.C. 103 as being unpatentable over Li (US2017/0291955, published 10/12/2017), in view of Croasdale (US2017/0029529, published 02/02/2017), Chen (US2018/0237496, published 08/23/2018), and Wang (US2016/0280795, published 09/29/2016).
Li teaches anti-Her2 binding molecules such as bispecific anti-Her2 antibodies and drug conjugates (Abstract). Pharmaceutical formulations comprising the disclosed compositions are taught (Abstract). Figure 7A shows a design that matches the elected species claim 25 in which scFvs that binds domain IV of Her2 are connected by linkers to the VH region of the 39S antibody. The 39S antibody binds domain II of human Her2 (0056). The second antigen binding site (scFv) can be that of trastuzumab which binds domain IV of human Her2 (0013).
With respect to claim 35, Li teaches at 0029-0031 the linker shown between each scFv and the antibody of Figure 7A and states that the linker can have 1-30 residues (0031).
With respect to claim 37, there is a linker shown between the VH and VL of the scFv of Figure 7A. Li teaches at 0028 the sequence of this linker as SEQ ID NO. 19 which has a subsequence of any of those in claim 39. Thus, claims 38-39 are anticipated by Li.
With respect to claim 44, Li teaches their bispecific antibody has an Fc region (shown in Figure 7A also) and it can be a mutant (0242-0243) and the Fc modification can reduce ADCC of the bispecific antibody (0244). L234F is an example (0244).
With respect to claim 46, Li teaches at 0038-0039 a hinge links CH1 and Fc regions and this is shown in Figure 7A also.
With respect to claim 149, Li teaches at 0053 a pharmaceutical composition with their Her2 bispecific antibody and a pharmaceutically acceptable carrier.
Li does not teach a specific linker between their scFv and the Fd of 39S.
Croasdale teaches very similar antibody designs to Li. See for example Figure 1B which is also an scFv-IgG fusion but the scFv is connected to the VL of the IgG instead of VH as in Li. However, a PHOSITA would have found it obvious to use the linkers of Croasdale in the design of Li since they are so similar as designs, are used for the same purpose, and it would have been no more than substituting one known linker for another by known recombinant DNA methods to arrive at predictable results, a functional bispecific antibody. Croasdale teaches at 0060 their linker can be (G4S)2 and so has a sequence of instant SEQ ID NO. 117 and SEQ ID NO. 118. Thus, for the reasons above use of this linker in the bispecific antibody of Li is obvious here and claim 36 would have been obvious before filing of the instant application.
Croasdale also teaches modifications to reduce effector function in their bispecific antibody (0244), which, like Li is a bispecific Her2 antibody (Abstract). The modifications can include L234A/L235A to reduce effector functions (0245). Such would accomplish the same goals as the L234F mutation-containing modification set in Li (Figure 8A of Li) and so it would have been obvious to a PHOSITA to use the combination of Croasdale instead, a simple substitution of one known set of effector function-reducing mutations for another to arrive at such functionality predictably. Such outcome is expected as the mutation combo reduces Fcgamma receptor binding which is needed for effector function of antibodies like IgG1 into which the mutations are taught (0245). Thus, instant claim 45 would have been obvious before filing of the instant application.
The prior art was well-aware of an Fc region with LALA mutations as taught by Chen.
Chen teaches polypeptides that binds a BBB receptor for transport across the BBB (Abstract). Their SEQ ID NO. 386 (0282) contains instant SEQ ID NO. 137 which would be recognized to carry the LALA mutation above as well as a knob mutation 366W by a PHOSITA. Since it carries LALA mutations, it would be applicable in the fusion above made obvious by the combination of Li and Croasdale, saving a PHOSITA time and economy in making their own LALA mutated Fc region de novo and so for these advantages it would have been obvious to them to use the one of Chen, which would give them a reasonable expectation of success at generating the obvious construct above. Thus, claims 47-49 are obvious here.
Equally obvious is the pairing of the knob containing Fc region of Chen with a hole-modified Fc region such as that of Wang.
Wang teaches their SEQ ID NO. 15 (0118) which contains a hole (Table 2). This sequence contains instant SEQ ID NO. 133 and so since use of the knob-Fc of Chen with the hole-Fc of Wang will predictably produce an Fc dimer as needed in the design of Li, it is obvious to use both together to arrive at the obvious molecule above. Thus, production of a bispecific anti-Her2 molecule with the design of Li, LALA mutations, and knob and hole technology of instant SEQ ID Nos. 133 and 137 would have been obvious to a PHOSITA. This practitioner would have enjoyed a reasonable expectation of success in making and using the obvious molecule to bind Her2 at both epitopes of Li, as these sequences would yield the Fc dimer desired, producing clearly a therapeutic anti-Her2+ cancer antibody since trastuzumab was well-known as such an agent and its binding domain is used in the obvious molecule here.
Thus, the combined teachings above clearly render the instant claims above obvious.
Claim(s) 25, 27, 29, 34-42, 44-49, and 149 are rejected under 35 U.S.C. 103 as being unpatentable over Li (US2017/0291955, published 10/12/2017), in view of Croasdale (US2017/0029529, published 02/02/2017), Chen (US2018/0237496, published 08/23/2018), and Wang (US2016/0280795, published 09/29/2016) as applied to claims 25, 27, 29, 34-39, 44-49, and 149 above, and further in view of Klein (US2020/0299407, with priority to 06/20/2016) and Movahedi (US2015/0335770, published 11/26/2015).
The combined teachings of Li, Croasdale, Chen, and Wang render obvious claim 27 for the reasons supra with the entire first 103 being incorporated here.
They do not teach the Fc region binding a transferrin receptor.
This deficiency is remedied by Klein.
Klein teaches trispecific antibodies that bind Her2 and a BBB receptor (Abstract) and pharmaceutical compositions comprising the same (Abstract). At 0052 they teach a trispecific antibody for Her2 and transferrin receptor that binds domains II and IV of Her2 and the transferrin receptor, one of which carries the LALA mutations above (0052). Clearly, since the obvious molecule in the first 103 has the same targets on Her2 as that of Klein, then it would have been obvious to substitute one known antibody against these two Her2 targets for another, using the obvious molecule in the design of Klein to arrive at a molecule with predictable functionality against Her2-expressing cancers in the CNS some of which are metastases of metastatic breast cancers (0008). Klein teaches existing therapies need improvement for these metastases, including toxicities and efficacies being issues thereof (0008). However, the obvious molecule would provide an additional treatment for said metastases and for the advantage of predictably, more aggressively treating said disease, the trispecific molecule here that can cross the BBB using the design features of Li and Klein would have been obvious to make.
Said obvious molecule carries instant SEQ ID Nos. 133 and 137 as discussed supra. Therefore, it carries in one Fc region T366W (SEQ ID NO. 137) and T366S, L368A, and Y407V in the other (SEQ ID NO: 133). Thus, the knob and hole technology of these sequences makes clear that claim 42 would have been obvious before filing of the instant application to a PHOSITA.
The examiner also notes there that a PHOSITA was well-aware of the advantage of streamlining anti-cancer antibody design by reducing size before the instant application was filed. Movahedi teaches due to their small size and high tumor penetrance, single domain antibodies are ideal for imaging tumors (0097) and this evidences the advantage above was known prior to instant application filing. Higher tumor penetrance will predictably lead to more antibody binding to more cancer cells for the advantage of better treating the tumor, such as a metastasis to the CNS as here. Thus, while the properties of the obvious molecule are desirable, one can also envision only one scFv being used from the design of Li, for example and/or only one transferrin receptor binding site being used, such as at the C-terminus of an Fc region as in Li at Figure 7B. Indeed, Klein teaches monovalency for this BBB receptor (0012). This would generate an asymmetry in the obvious molecule and so heterodimerization would be required of the Fc domains. The knob and hole technology will promote this (Croasdale at 0154 and 0220-0223), making use of Fc regions with instant SEQ ID Nos. 133 and 137 all the more obvious to a PHOSITA prior to filing.
Thus, the combined teachings above clearly render all claims above obvious.
Claim Rejections - Improper Markush Grouping
Claim 54 is rejected on the judicially-created basis that they contain an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
MPEP 803.02 provides guidance on the analysis of a proper Markush group. Members of a proper Markush group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. The MPEP further provides that in the members of a proper Markush group there should be (1) a common utility, and (2) a substantial structural feature essential to that utility.
In the instant case, claim 54 permits mutation of all CDRs in each construct embodiment. Furthermore, even without mutation it is not clear that all constructs share the same CDR sets to bind each of the two required domains of Her2 recited in claim 25. Therefore, within the Markush group listed, for both reasons above, no one CDR set for each target is required for each member of the group. As discussed above in the enablement rejection, all incorporated here, it is the CDR set that provides antigen binding function of an antibody and so this is the substantial structural feature shared among members of a proper Markush group of antibodies. Therefore, since this is lacking in claim 54, the Markush group is improper for each binding domain subgenus (binders of subdomain II and IV of human Her2) and the claim is rejected here.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1).
Conclusion
No claim is allowed.
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/Michael Allen/Primary Examiner, Art Unit 1642