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 .
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 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.
Priority
The instant application, filed 03/19/2024, is a 371 filing of PCT/US2022/076657, filed 09/19/2022, and claims domestic benefit to US provisional applications 63/332,034, filed 04/18/2022, and 63/246,279, filed 09/20/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 01/13/2025 is acknowledged. Claims 1-6, 8-9, 13, 23, 25, 32-33, 35-40, and 42 are amended and claims 7, 10-12, 14-22, 24, 26-31, 34, 41, and 43-49 are cancelled. Claims 1-6, 8-9, 13, 23, 25, 32-33, 35-40, and 42 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/14/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence listing filed on 01/13/2025, contains 4546 sequences; however, the specification and claims reference SEQ ID NOs that are beyond 4546. For instance, the instant claims reference SEQ ID NOs in the 5000s which are not included in the sequence listing. In the specification, page 105, sequences in the 11,000s are also referenced but not part of the sequence listing.
Furthermore, the sequences listed in the filing on 01/14/2025 do not all match the sequences in the specification for the provided SEQ ID NOs. For instance, SEQ ID NO: 3648 is referenced in the specification, on page 105, as being the amino acid sequence “PLNGAVHLY”; however, in the sequence listing, SEQ ID NO: 3648 is a DNA sequence, not an amino acid sequence, and is 2208 nucleotides in length.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
In the specification filed 01/13/2025, the incorporation by reference paragraph recites the listing size in kilobytes rather than the required bytes See 1.c and 2.c. above.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The specification filed 01/13/2025 recites sequences that are not accompanied by a SEQ ID NO in at least the following locations:
For instance, “(G4S)3” is recited in the following locations without a corresponding SEQ ID NO. It is note that this is not an exhaustive list and (G4S)3 is recited throughout the specification without SEQ ID NOs.
Page 15, line 20;
Page 18, lines 7, 14, and 20;
Page 23, line 30;
Page 24, lines 6, 12, and 20;
Page 25, lines 8 and 30;
Page 26, lines 2, 15, and 20;
Page 64, line 24;
Page 67, lines 4, 11, 17;
Page 69, line 22;
Page 151, line 35;
Page 255, line 25;
“G4S” is recited in at least the following locations without a corresponding SEQ ID NO. It is note that this is not an exhaustive list and (G4S)3 is recited throughout the specification without SEQ ID NOs.
Page 18, line 7;
Page 64, line 24;
Page 67, line 4;
Page 151, line 35
Page 152, lines 17 and 33;
Page 53, line 4, recites “TLAVPFK” without a SEQ ID NO;
“GCATGC” is recited in the following locations without a corresponding SEQ ID NO:
Page 132, line 30;
Page 133, line 5;
Page 134, line 21;
Page 135, lines 13, and 31;
Page 136, line 23;
Page 137, lines 4, 20, and 32;
Page 138, line 7
Page 136, line 23; page 137, lines 4, 20, and 32; and Page 138, line 7 recite “GGAT” and “CACGTG” without SEQ ID NOs;
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure filed 01/13/2025 is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Page 308 of the specification filed 01/13/2025 recites the following sequence. The prefix and non-top level domain executable code has been bolded for clarity:
https://doi.org/10.1038/s41573-021-00139-y
Appropriate correction is required.
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 5, 8-9, 13, and 37 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 5 recites “optionally wherein the Fc region:…”. As recited in the claim, the use of “optionally” renders the metes and bounds of the claim indefinite as it is unclear if the limitations that follow the term are part of the claimed invention or exemplary embodiments thereof. Furthermore, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “Fc region or functional variant thereof”, and the claim also recites the optional limitations which further limit the Fc region or functional variants thereof which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
In the rejections of the instant office action, the optional limitations are interpreted as not being required.
Claim 5 recites the limitation “The nucleic acid of claim 4, which encodes an Fc region or functional variant thereof”. Claim 5 depends on claim 4 which recites the isolated nucleic acid of claim 1 and further limits the encoded antibody molecule to being full length antibody, a bispecific antibody, a Fab, a F(ab’)2, a Fv, a scFv, a single domain antibody, or a camelid antibody. Claim 1 is drawn to an isolated nucleic acid comprising a transgene that encodes an antibody molecule binding to HER2/neu comprising a VH and VL region. Claims 1 and 4 do not explicitly recite a nucleic acid which encodes an Fc region or functional variant thereof. As such, it is unclear if the limitation in claim 5 is intended to further require that the nucleic acid encode an Fc region or functional variant thereof, regardless of the structure of the antibody molecule, or if the limitation is intended to limit the antibody molecules recited in claim 4 to being one that has an Fc region, such as a full-length antibody. As the metes and bounds of the claim are unclear, the claim is indefinite.
Claim 8 recites the limitations “the heavy chain" and “the light chain” in lines 4 and 7, respectively. There is insufficient antecedent basis for these limitations in the claim. Claim 8 depends on claim 1 which recites a transgene encoding a VH and VL with the recite sequences. Neither claim 1 nor 8 recite a heavy chain or a light chain that could be being referenced. While VH and VL can be included in a heavy and light chain, recitation of VH and VL does not necessarily include a heavy and light chain.
Appropriate correction is required.
Claim 9 recites “the sequences of the encoded heavy chain and light chain” in parts (iii) and (iv). There is insufficient antecedent basis for these limitations in the claim. Claim 9 depends on claim 1 which recites a transgene encoding a VH and VL with the recite sequences. Neither claim 1 nor 8 recite a heavy chain or a light chain that could be being referenced. While VH and VL can be included in a heavy and light chain, recitation of VH and VL does not necessarily include a heavy and light chain.
Appropriate correction is required.
Claim 13 recites the limitation “optionally wherein (i) the first antigen binding domain….”. As recited in the claim, the use of “optionally” renders the claim indefinite as it is unclear if the limitations that follow, which are narrower embodiments of the preceding limitation, are part of the claimed invention or exemplary embodiments thereof. Furthermore, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “at least two antigen binding domains for two different domains of HER2”, and the claim also recites the optional limitations in parts (i) – (vi) which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
In the rejections of the instant office action, the optional limitations are interpreted as not being required.
Claim 37 recites “optionally wherein the cell is a mammalian cell, an insect cell, or a bacterial cell.” The use of “optionally” in the claim renders the claim indefinite as it is unclear if the limitations that follow are part of the claimed invention or exemplary embodiments thereof. Furthermore, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 37 recites the broad recitation “A cell”, and the claim also recites the “mammalian cell, an insect cell, or a bacterial cell” which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Appropriate correction is required.
In the rejections of the instant office action, the optional limitations are interpreted as not being required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 depends on claim 1 and encompasses embodiments in which the encoded antibody molecule is a single domain antibody or a camelid antibody. Single domain antibodies and camelid antibodies are art recognized single chain, VHH domain antibodies that do not comprise a light chain or a light chain variable region. This definition is further supported by the instant specification, which identifies single domain antibodies as including heavy chain antibodies and antibodies that are devoid of a light chain. The specification also identifies that such a VHH molecule can be derived from antibodies raised in Camelidae species (page 144, lines 19-30). Instant claim 1, however, requires that the antibody comprise both a VH and VL region having the sequences recited in (a) or (b). As the embodiments of claim 4 in which the encoded antibody molecule is a single domain antibody or a camelid antibody only require the antibody to comprise a variable heavy chain devoid of a light chain, the claim does not include all of the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-6, 8-9, 13, 23, 25, 32-33, 35-40, and 42 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 1 is drawn to an isolated nucleic acid comprising a transgene encoding an antibody molecule that binds HER2/neu, comprising a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH and VL are as recited in (a) or (b). Both (a)(i) and (b(i) claim that the nucleotide sequence encoding the VH comprises the recited sequences “or a nucleotide sequence with at least 90% identity” to the recited sequences. Similarly (a)(ii) and b(ii) claim that the nucleotide sequence encoding the VL comprises the recited sequence “or a nucleotide sequence with at least 90% sequence identity” to the recited sequences. As such, the claim is drawn to a genus of nucleotide structures encoding VH and VL which are claimed with the function of binding HER2/neu. Claim 42 also requires that the antibody be capable of treating a subject having or diagnosed with having cancer expressing HER2/neu.
Claim 3 depends on claim 1 and further recites sequences for the heavy chain and the light chain of the antibody molecule. Parts (a)(i) and (b)(i) recites that the nucleotide sequence encoding the heavy chain comprises the recited sequences “or a nucleotide with at least 90% sequence identity” to the recited sequences. Similarly, parts (a)(ii) and (b)(ii) recite that the nucleotide sequence encoding the light chain comprises the recited sequences “or a nucleotide with at least 90% sequence identity” to the recited sequences. As such, the claim remains drawn to the genus of nucleotide structures recited in claim 1 and also encompass the function of binding HER2/neu.
As discussed above, based on the recitation of “or a nucleotide sequence with at least 90% sequence identity”, the instant claims are drawn to a genus of nucleotide sequences and antibody molecules encoded therefrom all of which are claimed with the functional limitation of binding to HER2/neu and treating a subject with cancer expressing HER2/neu. The claims; however, do not limit how/where the nucleotide sequence is modified and, in the broadest reasonable interpretation of the claim, all allowable variation could occur in the CDRs of the antibody VH and VL, which are the art recognized binding site of antibodies.
The instant disclosure, however, does not identify a representative number of species of the instantly claimed genus resulting in the claimed function, nor does the disclosure identify a structure-function correlation that could be used to predictably identify which modifications in the nucleotide sequences recited would maintain the claimed functions. This is particularly the case in the absence of a full complement of 6 CDRs (three from the heavy chain variable region and three from the light chain variable region) with 100% sequence identity that is demonstrated as binding HER2/neu.
The instant disclosure identifies the instantly claimed nucleic acids as encoding exemplary anti-HER2 antibodies:
Ab-HER-53 (pages 182-183) which has a VH DNA of SEQ ID NO: 5109 and a VL DNA of SEQ ID NO: 5113 and a heavy chain DNA of SEQ ID NO: 5111 and a light chain DNA of SEQ ID NO: 5115; and
Ab-HER-75 (pages 191-192) which has a VH DNA of SEQ ID NO: 5269 and a VL DNA of SEQ ID NOs: 5273 or 5245 and a heavy chain DNA of SEQ ID NOs: 5271 or 5244 and a light chain DNA of SEQ ID NOs: 5275 or 5246.
The examples of the instant disclosure, starting on page 329 of the specification filed 01/13/2025, the generation of anti-HER2 monospecific antibody molecules is disclosed. Example 1 describes genetic element constructs designed for AAV delivery of anti-HER2 antibodies. The antibodies used in the constructs include HER-53 and HER-75. Each of the constructs comprised a nucleic acid comprising a transgene encoding and antibody that binds HER2. Example 2 details codon optimization of the sequences encoding the anti-HER2 monospecific antibody molecules (page 330). In the example, it is disclosed that anti-HER2 monospecific antibody molecule HER-53 was codon optimized to eliminate a total of 87 dinucleotides in the transgene. The expression of codon optimized HER-75 was compared to HER-53 and HER-77 in HEK expi293 cells and is shown in Figs. 1A and 1B.
Ab-HER-53 and Ab-HER75, with a full complement of 6 CDRs (3 from the VH and 3 from the VL) are the species of the instantly claimed genus that applicant was in possession of at the time of filing.
These species are not representative of the full scope of the instantly claimed genus in which the modifications can be made anywhere in the claimed nucleic acid sequences, including in the region of the antibody CDRs. The disclosure also does not provide a sufficient structure function correlation that would allow for the predictable identification of which nucleic acids in the nucleotide sequences could be modified while maintaining HER2/neu binding.
The prior art also does not provide a representative number of species of the claimed genus binding to HER2/neu, nor does the prior art provide a structure function relationship that could be used to predictably identify which nucleotides could be modified while retaining this binding. Rather, the art suggests that antibody structure-function is not predictable, particularly in antibody CDRs.
For instance, Chiu, M.L., et al (2019) Antibody structure and function: The basis for engineering therapeutics Antibodies 8(55); 1-80 teaches that, the antigen-binding site of immunoglobulins is formed by the pairing of the variable domains (VH and VL) of the Fab region. Chiu teaches that each domain contributes three complementarity determining regions (CDRs), specifically, three from the VL and three from the VH, and that the six CDR loops are in proximity to each other resulting from the orientation of the VL and VH regions. Chiu teaches that the configuration of the VL and VH brings the three CDRs of the VL and VH domains together to form the antigen-binding site (page 4, paragraph 2). These teachings of Chiu demonstrate that the interaction between the heavy and light chain variable domains effect the conformation of the binding region of the antibody and therefore the antibody’s ability to bind to its target. Furthermore, the teachings of Chiu point out that the binding site is formed by the combination of the heavy and light chain CDRs (six regions) together. Based on these teachings, an ordinarily skilled artisan would not have been able to predictably identify which species of the instantly claimed genus would be capable of performing the claimed function. This is particularly the case in the absence of a full complement of heavy and light chain CDRs.
Rabia, L., et al (2018) Understanding and overcoming trade-offs between antibody affinity, specificity, stability, and solubility Biochem Eng. J. 15(137); 365-374 discusses challenges faced during antibody optimization. Rabia discusses the challenges with optimizing antibody properties and states that “natural antibody affinity maturation relies on the introduction of somatic mutations followed by clonal selection of antibody variants with improved affinity. However, not all somatic mutations contribute to antibody affinity… antibodies accumulate some somatic mutations to increase affinity and others to compensate for the destabilizing effects of affinity-enhancing mutations” (page 2, paragraph 4). Rabia further provides an example of researchers who introduced mutations throughout variable frameworks and CDRs and created libraries to sort antibody variants with high antigen binding. In this case an antibody was identified that displayed increased affinity but had a significant reduction in stability (page 3, paragraph 2). Rabia concludes by stating that “a final key area of future work is the development of improved computational methods for predicting mutations in antibody CDRs and frameworks that co-optimize multiple antibody properties” and that “future efforts will also need to improve structural predictions of antibody CDRs – especially the long and highly variable heavy chain CDR3 – to accurately predict CDR mutations that are beneficial to different antibody properties” (page 9, paragraph 4 – page 10 paragraph 2).
Based on the teachings of Rabia, introducing mutations in the antibody structure, particularly in the CDR regions, is not a predictable task and requires experimentation following mutation to ensure that the binding affinity is maintained and a specific, stable antibody is created. Rabia further spoke to the use of libraries and computational methods for predicting and co-optimizing antibody properties and teaches that these methods are not robust enough yet to yield predictable results. These teachings demonstrate that a modification to even one amino acid of an antibody, particularly in the CDRs, would likely result in an antibody that is not suitable for binding as recited in the instant claims.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately a year after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1). Teachings which demonstrate that even after the effective filing date of the claimed invention even modifications, even those using conservative substitutions, were not predictable.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire genus of antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable substitution of nucleic acids that would result in amino acid changes in the claimed sequences, particularly in the CDRs, while maintaining binding function. Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there is support for variation in the portion of the nucleotide sequence encoding the framework regions in the heavy and light chain variable domains of the antibody if the full complement of 6 CDRs were limited to 100% identity.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 9, 23, 25, 32-33, 35-40, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over CN 102030827 A (Guo, Y., et al) 27 Apr 2011 English translation from https://worldwide.espacenet.com/ on 22 July 2026 and US 2019/0224339 A1 (Paul. S., et al) 25 July 2019.
CN’827 teaches the nucleotide and amino acid sequences of the variable regions of the heavy and light chains of trastuzumab (page 31, [0041]; figure 1) and also discloses mutants of trastuzumab. CN’827 teaches that Fig. 1 shows the nucleotide and amino acid sequences of the variable regions of the heavy and light chain variable regions of trastuzumab (page 31, [0041]).
The VH nucleic acid sequence disclosed by CN’827 in Fig. 1 is identical to instant SEQ ID NO: 5109, as shown in the alignment below:
PNG
media_image1.png
544
613
media_image1.png
Greyscale
The VL nucleic acid sequence disclosed by CN’827 in Fig. 1 is 98.5% identical to instant SEQ ID NO: 5109, as shown in the alignment below:
PNG
media_image2.png
542
628
media_image2.png
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As shown, the VL nucleic acid sequence is 98.5% identical to instant SEQ ID NO: 5113 with 3 mismatches which meets the instant claim 1 limitation of at least 90% sequence identity to the nucleotide sequence of SEQ ID NO: 5113.
CN’827 teaches that the antibodies were constructed using overlap PCR and the construction, expression, and purification methods were the same as those for unmutated humanized trastuzumab (WT) (page 17). Primers were designed based on the reported sequences to amplify the antibody heavy and light chain constant regions using PT-PCR. The PCR product was purified and recovered by agarose gel electrophoresis and cloned into pGEM-T vectors. Sequence verification confirmed that the correct clone was retained (pages 29-30). Example 2 teaches the construction of an expression vector for anti-HER2 humanized antibody trastuzumab (page 30, [0040]). Humanized antibody heavy chain genes were synthesized by overlap PCT using Her2VH gene and pGEM-T/CH vector templates. The humanized heavy chain gene contains a restriction enzyme site HindIII and the signal peptide gene sequence at its 5’ end, and the translation termination codon TAA at the restriction enzyme site EcoRI at its 3’ end. The signal peptide is sequence is provided (pages 31-32). The PCR amplification products were separated by agarose gel electrophoresis, the target band was recovered and cloned into the pGEMT vector. Positive clones were screened and sequenced. Clones with correct sequencing were selected and digested with HindIII and EcoRI. The humanized antibody heavy chain fragment Her2VHCH was purified and recovered by agarose gel electrophoresis and ligated with the plasmid pcDNA3.1(+) and digested with HindIII and EcoRI to construct the humanized heavy chain eukaryotic expression vector pcDNA3.1(+)(Her2VHCH) (pages 31-32). A similar method is disclosed for the light chain genes.
CN’827 also discloses that the heavy chain and light chain constant region genes of the anti-HER2 humanized antibody were also constructed and, through construction and purification, the humanized trastuzumab antibody was constructed (page 17), indicating that the antibody produced was a full-length antibody.
CN’827 teaches that HER2 is a target for breast cancer treatment and that HER2 expression levels are associated with the pathogenesis and prognosis of breast cancer. Additionally, the HER2 expression level and gene copy number in tumors are much higher than in normal tissues, effectively reducing the toxicity of HER2-targeted therapy drugs. The proportion of HER2-positive tumor cells is also very high and HER2 is highly expressed on the surface of tumor cells so it can target most tumor cells in the patient’s body. HER2 is also expressed in both primary tumors and metastatic lesions, therefore HER2-targeted therapy is effective for both primary and metastatic lesions (page 4, [0005]). CN’827 teaches that trastuzumab in combination with paclitaxel is FDA approved as a first-line treatment for HER2/neu-overexpressing metastatic breast cancer, or as a monotherapy for the treatment of HER2/neu-overexpressing metastatic breast cancer that has undergone at least one cycle of chemotherapy. Trastuzumab not only has a high affinity for the HER2 receptor, but also solves the immunogenicity problem of applying murine antibodies to humans. Compared to chemotherapy alone, patients with advanced recurrent breast cancer have longer survival and lower mortality rates (pages 4-5, [0006]).
Isolated nucleic acids disclosed by CN’827 differ from the instantly claimed invention in that CN’827 does not disclose that the VH and VL are encoded by the same transgene in the same isolated nucleic acid.
US’339 teaches compositions and methods for the preparation, manufacture, and therapeutic use of viral vectors, such as adeno-associated virus (AAV) particles having viral genomes encoding one or more antibodies or antibody fragments or antibody like polypeptides, for the prevention and/or treatment of diseases or disorders (abstract).
US’339 teaches that antibodies have been approved by the FDA for the treatment of diseases including cancers (page 1, [0004]); however, antibodies have relatively short half-lives and this presents an ongoing and long-felt challenge for antibody based therapies. In order to achieve a sufficiently high concentration of an antibody for long lasting therapeutic effects, antibody therapies are traditionally delivered by repeat administration, e.g., by multiple injections. This dosing regimen results in an inconsistent level of antibody throughout the treatment period, limited efficacy per administration, high cost of administration and consumption of the antibody. US’339, therefore, provides alternative delivery routes or modalities of administration (page 1, [0005]). One such alternative route of administration is by expression vectors, e.g., plasmid or viral vectors, including but not limited to, adeno-associated viral vectors (AAVs) (page 1, [0005]).
US’339 teaches AAV particles comprising a capsid and a viral genome, said viral genome comprising at least one inverted terminal repeat (ITR) region and a payload region, said payload region comprising a regulatory sequence operably linked to at least a first nucleic acid segment encoding one or more polypeptides (page 1, [0011]). The first nucleic acid segment may encode one or more polypeptides such as an antibody heavy chain, an antibody light chain, a linker, and combinations thereof. The first nucleic acid segment may encode one or more polypeptides which are humanized. As a non-limiting example, US’339 teaches that the first nucleic acid segment encodes, from 5’ to 3’, an antibody heavy chain, a linker, and an antibody light chain. Alternatively, from 5’ to 3’, the segment can encode an antibody light chain, a linker, and an antibody heavy chain (page 2, [0012]). US’339 provides a schematic of the viral genome in Fig. 2 and Fig. 3 provides a schematic of potential payload regions (page 3, [0036]-[0037]; Figs 2-3). Fig. 2 is replicated below for convenience:
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In Fig. 2, the payload region, 110, is located within the viral genome, 100. At the 5’ and/or 3’ end of the payload region 110 there may be at least one inverted terminal repeat (ITR) 120. Within the payload region there is a promoter region 130, an intron region 140, and a coding region 150. When the coding region 150 comprises a heavy chain region 151 and a light chain region 152, the two chains may be separated by a linker region 155 (page 56, [0177]).
US’339 teaches that the payload regions may optionally comprise a linker between the light and heavy antibody chain sequences or polypeptides. Sequences encoding linkers are derived from IRES, foot and mouth disease virus 2A (F2A), porcine teschovirus-1 virus 2A (P2A), a furin cleavage site (F), or a 5xG4S linker sequence. Alternatively, the order of the heavy and light chain can be altered with respect to the 5’ to 3’ direction (page 166, [0685]).
US’339 further teaches that the payloads can encode polypeptides that form one or more functional antibodies or antibody-based compositions, including monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies formed from at least two intact antibodies) and antibody fragments (page 56, [0181]). Alternatively, the payloads can be antibody fragments including Fab, Fab’, F(ab’)2, and Fv fragment, as well as diabodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments (page 60, [0208]). US’339 also teaches that the transgene can encode a fynomer (page 61, [0222]).
US’339 further teaches that the payload region can comprise at least one element to enhance the transgene target specificity and expression. Non-limiting examples of elements that enhance the transgene target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs), polyadenylation (PolyA), signal sequences and upstream enhancers (USEs), CMV enhancers, and introns (pages 19-20, [0096]). Signal sequences are sequences that can direct the transport or localization of a protein (page 163, [0641]). US’339 further teaches optimization of the encoded antibody and teaches that, to improve secretion of the antibody, the endogenous signal sequences are replaced with a sequence that may or may not be codon optimized, derived from any gene. In some cases the human growth hormone signal sequence is used. Any of the heavy, light, or both chains, may be driven by any signal sequence, whether the same or different (page 166, [0683]).
US’339 teaches that the payloads are designed to encode protein signal sequences to aid in protein processing, localization, and/or secretion, as well as an untranslated poly A tail (page 166, right column, [0685]).
US’339 teaches that the viral genome can also comprise a ubiquitous promoters, such as CMV, CBA (including derivatives CAG, CBh, etc), EF-1a, PGK, UBC, GUSB, and UCOE (page 21, [0108]); or a tissue specific expression element used to restrict expression to certain cell types (page 2, [0014]).
US’339 exemplifies constructs comprising a 5’ ITR of SEQ ID NO: 4270, a CB6 promoter, a SV40 intron, a rabbit goblin poly A tail of SEQ ID NO: 4273, and a 3’ ITR sequence of SEQ ID NO: 4274 (page 167, [00693]).
US’339, SEQ ID NO: 4270 is identical to instant SEQ ID NO: 2076, as shown in the alignment below:
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US’339, SEQ ID NO: 4274 is identical to instant SEQ ID NO: 2078, as shown in the alignment below:
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US’339, SEQ ID NO: 4273 is identical to instant SEQ ID NO: 2122, as shown in the alignment below:
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US’339 further teaches that the AAV particles comprise a capsid and a viral genome, said viral genome comprising at least one ITR region and the payload region. US’339 also teaches that capsid of the AAV particle may be any of the sterotypes described and/or those described in Table 1 (pages 1-2, [0011]), which includes AAVPHP.B, AAV1, AAV2, AAV5, AAV9, or AAVrh.10 (Table 1, pages 11-19).
US’339 further teaches that AAVs may be introduced into a wide variety of host cells, do not integrate into the genome of the host cell, and are capable of infecting both quiescent and dividing cells. AAVs transduce non-replicating and long lived cells in vivo, resulting in long term expression of the protein of interest. Further, AAVs can be manipulated with cellular and molecular biology techniques to produce non-toxic particles carrying a payload encoded in the AAV viral genome that can be delivered to a target tissue or set of cells with limited or no side effects. Given the foregoing, the use of AAVs for vectored antibody delivery would allow for longer lasting efficacy, fewer dose treatments, and more consistent levels of antibody throughout the treatment period (page 1, [0006]).
US’399 teaches that the AAV particles comprising a payload region encoding the polypeptides can be introduced into mammalian cells (page 5, [0058]). US’399 also teaches that DNA can be expressed in insect or mammalian cells (page 59, [0204]) and bacterial cells (page 127, [0373]).
US’399 teaches a method of making an AAV particle comprising the steps of: 1) co-transfecting competent bacterial cells with a bacmid vector and either a viral construct vector and/or an AAV payload construct vector, 2) isolating the resultant viral construct expression vector and AAV payload construct expression vector and separately transfecting viral replication cells, 3) isolating and purifying resultant payload and viral construct particles comprising viral construct expression vector or AAV payload construct expression vector, 4) co-infecting a viral replication cell with both AAV payload and viral construct particles and 5) harvesting and purifying the AAV particle comprising a viral genome (page 127, [0373]).
US’399 teaches an alternative method for producing an AAV particle comprising the steps of 1) simultaneously co-transfecting mammalian cells, such as, but not limited to, HEK293 cells, with a payload region, a construct expressing rep and cap genes and a helper construct, and 2) harvesting and purifying the AAV particle comprising a viral genome (page 127, [0374]).
US’399 also teaches that the AAV particles can be prepared as pharmaceutical compositions comprising one or more active ingredients and, most often, a pharmaceutically acceptable excipient (page 127, [0377]).
US’399 also teaches a method of delivering to a subject, including a mammalian subject, the AAV particles comprising administering to the subject said AAV particle or administering to the subject a formulation or pharmaceutical composition comprising the AAV particle (page 136, [0453]).
US’399 also teaches that various cancers can be treated with the AAV particles and compositions, including breast cancer (page 150, [0498]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the nucleic acid and methods disclosed by CN’827 by using the AAV vectored antibody delivery constructs and methods disclosed by US’339 for the production and administration of the antibody. An ordinarily skilled artisan would have been motivated to use the constructs and methods of US’339 as US’339 teaches that the use of AAVs for vectored antibody delivery would allow for longer lasting efficacy, fewer dose treatments, and more consistent levels of the antibody throughout the treatment period overcoming the relatively short half-lives of antibodies. An ordinarily skilled artisan would have had a reasonable expectation of success as US’399 teaches methods of encoding and delivering antibodies and CN’827 is also drawn antibodies. Additionally, US’399 teaches that the AAVs and compositions thereof can be used to in methods of treating diseases including cancer including breast cancer, which CN’827 teaches can be treated by administration of the HER2/neu antibodies disclosed.
Alternatively, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the AAV vectored antibody delivery constructs and methods disclosed by US’339 by substituting the disclosed antibody VHs and VLs with the HER2/neu binding VH and VL / heavy and light chains nucleotide sequences disclosed by CN’827. An ordinarily skilled artisan would have been able to substitute the antibody VH and VL / heavy and light chains and would have had a reasonable expectation of success as US’339 teaches constructs and methods for encoding and delivery of antibodies and CN’827 is teaching antibodies that are encoded from nucleic acids and delivery of such antibodies for the treatment of diseases. Additionally, US’399 teaches that the AAVs and compositions thereof can be used to in methods of treating diseases including cancer including breast cancer, which CN’827 teaches can be treated by administration of the HER2/neu antibodies disclosed.
Regarding claim 2, CN’827 further teaches the nucleotide sequence of the light chain constant region of the human antibody (page 46, [0066] – page 51, [0082]), which has 96.1% identity with instant SEQ ID NO: 5007, as shown in the alignment below.
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Regarding claim 3, the antibody VL taught by CN’827, Fig. 1, combined with the nucleotide sequence of the light chain constant region of the human antibody taught by CN’827 (page 46, [0066] – page 51, [0082]) has 98.8% identity to instant SEQ ID NO: 5115, as shown in the alignment below:
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Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over CN 102030827 A (Guo, Y., et al) 27 Apr 2011 English translation from https://worldwide.espacenet.com/ on 22 July 2026 and US 2019/0224339 A1 (Paul. S., et al) 25 July 2019 as applied to claim 1 above, and in further view of Haryadi, R., et al (2015) Optimization of heavy chain and light chain signal peptides for high level expression of therapeutic antibodies in CHO cells PLOS ONE 10(2); e0116878; 1-16.
The combination of CN’827 and US’339 teach the isolated nucleic acid of claim 1 as discussed in detail above.
As discussed above, US’339 teaches that to improve the selection of the antibody, the endogenous signal sequences are replaced with a sequence which may or may not be codon optimized, derived from any gene. Any of the heavy, light, or both chains may be driven by any sequence signal, whether the same or different (page 166, [0683]). US’339 teaches that signal sequences are sequences that direct the transport or localization of a protein (page 163, [0641]).
The combination of CN’827 and US’339; however, do not disclose that the signal sequences are SEQ ID NO: 5157 located 5’ the VH nucleotide or SEQ ID NO: 5159 located 5’ the VL nucleotide.
Haryadi teaches that human IgG antibodies consist of two identical heavy chains and two identical light chains. Efficient expression of the HC and LC requires appropriate signal peptides for the transport of the HC and LC polypeptides to the endoplasmic reticulum for proper folding, assembly, and post-translational modification. Haryadi teaches that five top-selling therapeutic antibodies which are also biosimilar candidates for many biotech companies, including Herceptin (trastuzumab), were used as model molecules and a study was performed generating a signal peptide database of human antibody heavy and light chains. Using a bioinformatics approach, the signal peptides were cultured based on sequence similarity and the signal peptides were optimized for production in CHO cells (page 2, paragraph 4). Based on screening results, eight HC signal peptides and two LC signal peptides were chosen and compared for their impact on antibody secretion. The signal peptides are shown in Table 1 (page 3, paragraph 1; page 4, Table 1).
The DNA sequences of the HC signal peptide identified as H5 is identical to instant SEQ ID NO: 5157, as shown in the alignment below:
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The DNA sequence of the LC signal peptide identified as L1 is identical to instant SEQ ID NO: 5159, as shown in the alignment below:
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Haryadi further teaches that the results in Fig. 2 show that the best signal peptide combination for the production of Herceptin (trastuzumab) includes H5/L1 (page 6, paragraph 4; page 7, Fig. 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the nucleic acid taught by the combination of CN’827 and US’339 by substituting the signal peptide controlling the HC and LC nucleotide sequences with the H5 and L1 signal peptides of Haryadi, respectively. An ordinarily skilled artisan would have been motivated to use the H5/L1 signal peptides of Haryadi because Haryadi demonstrates that, for the production of Herceptin (trastuzumab), this combination of signal peptides was one of the best signal peptide combination in mammalian cells. An ordinarily skilled artisan would have had a reasonable expectation of success as CN’827 teaches that the antibody is trastuzumab and US’339 teaches that the VH and VL can both be controlled by signal peptides that direct the transport or localization of a protein. US’339 also teaches that the AAV particles comprising the antibody payload can be introduced into mammalian cells.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/106158 A1 (Gao, Z., et al) 30 June 2016 and US 2019/0224339 A1 (Paul. S., et al) 25 July 2019.
WO’158 teaches a bispecific tetravalent antibody comprising an IgG having a pair of heavy chains and a pair of light chains and two scFv components connected to either the C-or N-terminals of the heavy or light chains. The bispecific tetravalent antibody may have a binding specificity for two epitopes on HER2 receptor (abstract).
WO’158 teaches that HER2 is a member of the ErbB/HER receptor family and is overexpressed and/or deregulated in several cancers of the breast and ovary. Therapeutics targeting HER2 have been used successfully in the clinic and have been approved by the US FDA. Such antibody therapeutics include trastuzumab and pertuzumab. Several studies have indicated that therapeutic enhancement may be achieved by combining two or more epitope-distinct ant-HER2 antibodies such as trastuzumab and pertuzumab compared to single antibody monotherapy. Trastuzumab, which binds to the extracellular domain 4 of HER2, inhibits ligand independent signaling, stimulates ADCC, blocks HER2 shedding but does not inhibit HER2 dimerization. Pertuzumab, which binds the extracellular domain 2 of HER2, inhibits HER2 dimerization and dimerization with other HER family receptors, inhibits multiple ligand-dependent HER mediated signaling pathways and stimulates ADC (page 1, line 20 – page 2, line 8). WO’158 teaches that a combination of pertuzumab and trastuzumab for the treatment of HER2 positive breast cancer was approved by the FDA in 2013; however, the efficacy of the use of the simple combination of two or more monoclonal antibodies is sub-optimal. In addition the cost of producing two or more monoclonal antibodies separately is high (page 2, lines 9-15).
WO’158, therefore, discloses bispecific tetravalent antibodies that can comprise two IgG1 heavy chains; two kappa light chains; and two single chain Fv (scFv) domains. The two IgG1 heavy chains and kappa light chains may form an IgG moiety with a binding specificity to a first domain of HER2 and the two scFv domains may have a binding specificity to a second domain of HER2 (page 1, lines 20-21). WO’158 teaches that the domain of HER2 are 2 and 4 (page 5, 18-22).
WO’158 further teaches isolated nucleic acids encoding the bispecific tetravalent antibodies as well as vectors having the isolated nucleic acids and host cells expressing the vectors or isolated nucleic acids. WO’158 further teaches that the host cell may be procaryotic or eukaryotic (page 7, line 29 – page 8, line 10).
WO’158 teaches that, to construct the bispecific tetravalent antibodies, variable light chain, variable heavy chain and scFv DNA fragments were generated by gene synthesis. Human gamma-1 heavy chain and human kappa light chain DNA fragments were generated by gene synthesis. The two fragments were assembled together by DNA ligation using restriction sites and cloned into a vector that is designed for transient expression in mammalian cells. The vector contains a strong CMV-derived promoter and other upstream and downstream elements required for transient expression. Transient expression of the antibody constructs was achieved using transfection of suspension adapted HEK293F cells with linear PEI. Antibodies were purified from the resulting transfection supernatants using protein a affinity chromatography and size exclusion chromatography (page 11, lines 1-21).
WO’158; however, does not disclose that the nucleic acid is positioned between two inverted terminal repeats (ITRs).
The teachings of US’339 are as discussed in detail above.
US’339 teaches AAV particles comprising a viral genome with at least one ITR region and a payload region. In one embodiment, the viral genome has two ITRs. These two ITRs flank the payload region at the 5’ and 3’ ends. The ITRs function as origins of replication comprising recognition sites for replication (page 19, [0093]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the genetic construct disclosed by WO’158 by including two ITR regions flanking the bispecific tetravalent antibody at the 5’ and 3’ ends based on the teachings of US’399. Alternatively, it would have been obvious to use the nucleic acids encoding the bispecific tetravalent antibodies disclosed by WO’158 in the constructs and methods disclosed by US’399.
An ordinarily skilled artisan would have been motivated to include 5’ and 3’ ITRs as US’399 teaches that ITRs function as origins of replication comprising recognition sites for replication. An ordinarily skilled artisan would have had a reasonable expectation of success as both WO’158 and US’339 teach the use of vectors for the expression of antibody molecules. Additionally, US’339 teaches that the methods disclosed can be used in the production of bispecific antibodies and multispecific antibodies (page 157, [0559]) demonstrating applicability to the bispecific antibodies of WO’158.
Alternatively, an ordinarily skilled artisan would have been motivated to use the constructs and methods of US’339 as US’339 teaches that the use of AAVs for vectored antibody delivery would allow for longer lasting efficacy, fewer dose treatments, and more consistent levels of the antibody throughout the treatment period overcoming the relatively short half-lives of antibodies. An ordinarily skilled artisan would have had a reasonable expectation of success as US’399 teaches methods of encoding and delivering antibodies, including bispecific antibodies and WO’158 is also drawn to bispecific antibodies. Additionally, US’399 teaches that the AAVs and compositions thereof can be used to in methods of treating diseases including cancer including breast cancer, which WO’158 teaches can be treated by administration of the bispecific HER2 antibodies disclosed.
Additionally, it would have alternatively been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the AAV vectored antibody delivery constructs and methods disclosed by US’339 by substituting the disclosed antibody with the bispecific HER2 antibody nucleotide sequences disclosed by WO’158. An ordinarily skilled artisan would have been able to substitute bispecific antibody of WO’158 and would have had a reasonable expectation of success as US’339 teaches constructs and methods for encoding and delivery of antibodies, including bispecific antibodies and WO’158 is teaching antibodies that are encoded from nucleic acids and delivery of such antibodies for the treatment of diseases. Additionally, US’399 teaches that the AAVs and compositions thereof can be used to in methods of treating diseases including cancer including breast cancer, which WO’158 teaches can be treated by administration of the bispecific HER2 antibodies disclosed.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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