Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments and remarks, filed 01/16/2026, are acknowledged.
Claims 1-2, 4, 11-13, 15-16, 18-19, 21-27, 29-34, 37-40, 43-49, 52, 54, and 56-57 are canceled.
Claims 5-6, 8-10, 14, 17, 28, 41, and 50-51 are amended.
Claims 3, 5-10, 14, 17, 20, 28, 35-36, 41-42, 50-51, 53, 55, and 58-62 are pending.
DETAILED ACTION
Election/Restrictions
Applicant’s group election without traverse of Group I (claims 3, 5-10, 14, 17, 20, 28, 35-36, 41-42, 51, and 59) in the reply filed on 01/16/2026 is acknowledged.
Applicant’s species election without traverse of:
Six heterologous antigen epitopes:
GTGRAMLGTHTMEVTVYH (SEQ ID NO: 29);
SVYDFFVWL (SEQ ID NO: 30);
WNRQLYPEWTEAQRLD (SEQ ID NO: 31);
VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 32);
ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 33); and QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 34),
The following VH/VL sequences:
VH
QVQLVETGGGLIQPGGSLRMSCGTGRAMLGTHTMEVTVYHWVRQAPGKGLEWIAYIGSGGSVYDFFVWLRFTISRDNSKNTLYLQLNSLRAEDTAVYYCARVPLDCVLYRYGSFSVTLDIVQGWGQGTTVTVSS (SEQ ID NO: 2); and
VL
MGWSCIILFLVATATGVHSDVLMTQSPLSLPVTPGEPASISCWNRQLYPEWTEAQRLDWYLQKPGQSPQLLIYANCSVYDFFVWLHYYSVRDTLLGPGRPYRGVPDRFSGSGSGTDFTLKISRVEAEDTGVYYCQCTEVRADTRPWSGPYILRNQDDRELWPRKFFFGGGTKVEIK (SEQ ID NO: 10),
in the reply filed on 01/16/2026 is acknowledged.
Claims 50, 53, 55, 58, and 60-62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/16/2026.
As such, claims 3, 5-10, 14, 17, 20, 28, 35-36, 41-42, 51, and 59 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/23/2023 and 01/16/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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.
Drawings
The drawings are objected to because the title for Figure 19B recites “N 138-146 peptide”, but the description recites “N 138-147 peptide” (see page 52, line 8).
Additionally, the title for Figure 37D recites “Nyeso119-143 frequency”, but the description recites “Nyeso1 119-143” (see page 56, lines 24-29).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) 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 (e.g., see pages 50-64) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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 following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The disclosure is objected to because of the following informalities:
Page 11, line 20: “… amino acids in length, The linker…” should read “… amino acids in length. The linker…”.
Page 15, line 28: “anti-his antibody” should read “anti-His antibody”.
Page 48, line 28: “asterix” should read “asterisk”.
Page 49, line 1: “asterix” should read “asterisk”.
Page 50, lines 1, 7, 15, 23, and 31: “asterix” should read “asterisk”.
Page 51, lines 5, 13, and 22: “asterix” should read “asterisk”.
Page 51, lines 12 and 20: “igG3” should read “IgG3”.
Page 53, line 8: “SinoBiological” should read “Sino Biological”.
Page 53, lines 20, 26, and 32: “igG1” and “igG3” should read “IgG1” and “IgG3”, respectively.
Page 54, line 3: “igG3” should read “IgG3”.
Page 54, line 14: “inframe” should read “in frame”.
Page 54, lines 15 and 25: “igG1” should read “IgG3”.
Page 55, line 19: “xue et al.” should read “Xue et al.”.
Page 55, line 22: “igG1” should read “igG1”.
Page 58, lines 22 and 32-33: “igG1” and “igG3” should read “IgG1” and “IgG3”, respectively.
Page 60, line 20: “Genscript” should read “GenScript”.
Page 60, line 22: “Genescript” should read “GenScript”.
Page 63, line 10: “huigG1” should read “huIgG1”.
Page 66, line 6: “licence” should read “license”.
Page 67, line 2: “LifeTechnologies” should read “Life Technologies”.
Page 68, line 21: “Genescript” should read “GenScript”.
Page 69, line 7: “Genescript” should read “GenScript”.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 8 and 60). 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.
The use of the term IMGT, Biacore, GE Healthcare, Hiltonol, Sino Biological, GenScript, Miltenyi Biotec, Invitrogen, ImmunoBody, Taconic, ATCC, Sigma, Gibco, Life Technologies, Merck Millipore, Sigma Aldrich, Promega, Molecular Devices, Bright-Glo, SoftMax Pro, SpectraMax, FLUOstar, BMG Labtech, GraphPad Prism, Mabtech, Thermo Scientific, Acrobiosystems, Abzena, and Corning, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 3, 5, 6, and 28 are objected to because of the following informalities:
Claims 3(b), 5 and 6: “the Fc region” should read “the modified Fc region”.
Claim 5: “…D376, A378, optionally wherein…” should read “…D376, and A378; optionally wherein…”.
Claims 5 and 6: “D376, A378” should read “D376, and A378”.
Claim 28 should read “The nucleic acid of claim 3, wherein the nucleic acid is in combination with a second nucleic acid encoding at least one heterologous antigen”.
Appropriate correction is required.
Claim Interpretation
Claim 7 recites the transitional phrase “having”, the scope of which is not defined by the specification. As such, according to MPEP 2111.03(IV), the term will be interpreted as an open-ended transitional term, similar to the transitional phrase “comprising”. For example, the structure recited in the claims can comprise additional, unrecited elements.
Further, Examiner acknowledges that the term “heterologous antigen” is intended to mean an antigen which is heterologous to the modified Fc region (see page 16, lines 17-23).
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 3, 5-10, 14, 17, 20, 28, 35-36, 41-42, 51, and 59 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 3(c) recites “the modified Fc region has enhanced avidity for Fc-gamma receptor (FcγR) when compared to the corresponding wildtype Fc region”. It is unclear whether the wildtype Fc region is in reference to a wildtype human IgG1 or a wildtype mouse IgG3 antibody. As such claim 3 and its dependent claims are rejected.
The term “optionally” in claim 5 renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(h).
Claim 10 recites the limitations “any one of Figures 28-33” and “in Table 2 or Table 3”. This limitation incorporates a reference in the claim. MPEP2173.05(s) states:
Where possible, claims are to be complete in themselves. Incorporation by reference “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).
Examiner suggests reciting the sequences (i.e., SEQ ID Nos) of the epitopes recited in Figures 28-33, and Tables 2 and 3.
Claims 28 and 42 recite “a second nucleic acid encoding at least one heterologous antigen”. It is unclear whether the “at least one heterologous antigen” is the same heterologous antigen recited in claim 3, or if the limitation is drawn to a different antigen. As such, claims 28, 42, and their dependent claims are rejected.
Claim Rejections - 35 USC § 112(a) Written Description
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 3, 5-10, 14, 17, 20, 28, 35-36, 41-42, 51, and 59 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 3 is drawn to a nucleic acid which encodes a polypeptide comprising:(i) a modified Fc region of a human IgG1, and(ii) at least one heterologous antigen, wherein (a) the modified Fc region comprises at least the part of Fc that is capable of binding to CD64 and/or TRIM21, (b) at least one residue of the Fc region is modified to the corresponding residue from a mouse IgG3 antibody and (c) the modified Fc region has enhanced avidity for Fc- gamma receptor (FcyR) when compared to the corresponding wildtype Fc region.
Claim 5 is drawn to the nucleic acid of claim 3, wherein the at least one residue of the Fc region is selected from: N286, K288, K290, A339, Q342, P343, R344, E345, L351, S354, D356, E357, L358, T359, N361, Q362, K370, G371, Y373, P374, S375, D376, A378, optionally wherein the at least one modified residue is selected from: N286T, K288W, K290Q, A339P, Q342R, P343A, R344Q, E345T, L351I, S354P, D356E, E357Q, L358M, T359S, N361K, Q362K, K370T, G371N, Y373F, P374S, S375E, D376A, A378S.
Claim 6 is drawn to the nucleic acid of claim 5, wherein the Fc region of human IgG1 comprises all of the following modifications: N286T, K288W, K290Q, A339P, Q342R, P343A, R344Q, E345T, L351I, S354P, D356E, E357Q, L358M, T359S, N361K, Q362K, K370T, G371N, Y373F, P374S, S375E, D376A, A378S.
Claim 7 is drawn to the nucleic acid of claim 6, wherein the modified Fc region comprises the amino acid sequence provided in SEQ ID NO: 1, or an amino acid sequence having at least 90% identity to SEQ ID NO: 1.
Claim 8 is drawn to the nucleic acid of claim 3, wherein the at least one heterologous antigen is linked, directly or via a linker, to the N-terminus of the modified human IgG1 Fc region.
Claim 9 is drawn to the nucleic acid of claim 3, wherein the polypeptide further comprises an antibody variable region into which the at least one heterologous antigen is inserted or substituted, optionally wherein the at least one heterologous antigen is substituted into a CDR of the antibody variable region.
Claim 10 is drawn to the nucleic acid of claim 3, wherein the at least one heterologous antigen comprises a T cell epitope and/or a B cell epitope, and/or the at least one heterologous antigen is from a cancer or an infectious disease, and/or the at least one heterologous antigen comprises one or more epitopes selected from the epitopes set out in any one of Figures 28-33, and/or the at least one heterologous antigen comprises one or more epitopes selected from the epitopes set out in Table 2 or Table 3.
Claim 14 is drawn to the nucleic acid of claim 3, wherein the at least one heterologous antigen comprises one or more epitopes selected from: (a) GTGRAMLGTHTMEVTVYH (SEQ ID NO: 29);(b) SVYDFFVWL (SEQ ID NO: 30); and(c) WNRQLYPEWTEAQRLD (SEQ ID NO: 31), or one or more epitopes selected from:(a) GTGRAMLGTHTMEVTVYH (SEQ ID NO: 29);(b) SVYDFFVWL (SEQ ID NO: 30);(c) WNRQLYPEWTEAQRLD (SEQ ID NO: 31); and(d) VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 32), or one or more epitopes selected from:(a) GTGRAMLGTHTMEVTVYH (SEQ ID NO: 29);(b) SVYDFFVWL (SEQ ID NO: 30);(c) WNRQLYPEWTEAQRLD (SEQ ID NO: 31);(d) VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 32);(e) ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 33); and (f) QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 34).
Claim 17 is drawn to the nucleic acid of claim 3, wherein the at least one heterologous antigen comprises one or more epitopes selected from:(a) LLMWITQCF (SEQ ID NO: 35);(b) SLLMWITQC (SEQ ID NO: 36);(c) PESRLLEFYLAMPFATPMEAELARRSLAQ (SEQ ID NO: 37); and (d) PGVLLKEFTVSGNILTIRLTAADHR (SEQ ID NO: 38), or one or more epitopes selected from:(a) LLMWITQCF (SEQ ID NO: 35);(b) SLLMWITQC (SEQ ID NO: 36);(c) PESRLLEFYLAMPFATPMEAELARRSLAQ (SEQ ID NO: 37);(d) PESRLLEFY (SEQ ID NO: 39);(e) RLLEFYLAMPFATP (SEQ ID NO: 40);(f) LEFYLAMPF (SEQ ID NO: 41);(g) EFYLAMPFATPM (SEQ ID NO: 42);(h) MPFATPMEA (SEQ ID NO: 43);(i) LAMPFATPM (SEQ ID NO: 44);(j) LLEFYLAMPFATPM (SEQ ID NO: 45);(k) LLEFYLAMPFATPMEAELARRSLAQ (SEQ ID NO: 46);(1) PGVLLKEFTVSGNILTIRLTAADHR (SEQ ID NO: 38);(m) LKEFTVSGNILTIRL (SEQ ID NO: 47);(n) KEFTVSGNILT (SEQ ID NO: 48); (o) KEFTVSGNILTI (SEQ ID NO: 49); (p) TVSGNILTIR (SEQ ID NO: 50); and (q) TVSGNILTI (SEQ ID NO: 51).
Claim 20 is drawn to the nucleic acid of claim 9, wherein the antibody variable region is a heavy chain variable region comprising the following heterologous antigens substituted into the CDR1, CDR2 and CDR3 respectively:(a) GTGRAMLGTHTMEVTVYH (SEQ ID NO: 29), SVYDFFVWL (SEQ ID NO: 30) and VPLDCVLYRYGSFSVTLDIVQG (SEQ ID NO: 32); or (b) LLMWITQCF (SEQ ID NO: 35), SLLMWITQC (SEQ ID NO: 36) and PESRLLEFYLAMPFATPMEAELARRSLAQ (SEQ ID NO: 37).
Claim 28 is drawn to the nucleic acid of claim 3, in combination with a second nucleic acid encoding at least one heterologous antigen.
Claim 35 is drawn to the nucleic acid of claim 28, wherein the second nucleic acid encodes an antibody light chain into which the at least one heterologous antigen is inserted or substituted, optionally wherein the at least one heterologous antigen is substituted into a CDR of the antibody light chain.
Claim 36 is drawn to the nucleic acid of claim 35, wherein the antibody light chain encoded by the second nucleic acid comprises the following heterologous antigens substituted into the CDR1, CDR2 and CDR3 respectively: WNRQLYPEWTEAQRLD (SEQ ID NO: 31), ANCSVYDFFVWLHYYSVRDTLLGPGRPYR (SEQ ID NO: 33) and QCTEVRADTRPWSGPYILRNQDDRELWPRKFF (SEQ ID NO: 34), or the antibody light chain encoded by the second nucleic acid comprises the sequence PGVLLKEFTVSGNILTIRLTAADHR (SEQ ID NO: 38) substituted into the CDR2, or the antibody light chain encoded by the second nucleic acid comprises the amino acid sequence provided in SEQ ID NO: 10 or SEQ ID NO: 11, or the polypeptide encoded by the nucleic acid comprises the amino acid sequence provided in SEQ ID NO: 2 and wherein the antibody light chain encoded by the second nucleic acid comprises the amino acid sequence provided in SEQ ID NO: 10, or the polypeptide encoded by the nucleic acid comprises the amino acid sequence provided in SEQ ID NO: 3 and wherein the antibody light chain encoded by the second nucleic acid comprises the amino acid sequence provided in SEQ ID NO: 11.
Claim 41 is drawn to a vector comprising the nucleic acid of claim 3
Claim 42 is drawn to the vector of claim 41, wherein the vector further comprises a second nucleic acid encoding at least one heterologous antigen, and/or the vector is a DNA plasmid or doggybone (dbDNA) vector, and/or the vector comprises the nucleotide sequences of:(a) SEQ ID NO: 12 and SEQ ID NO: 13; or (b) SEQ ID NO: 14 and SEQ ID NO: 15; or (c) SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22.
Claim 51 is drawn to the vaccine composition comprising the nucleic acid of claim 3, optionally in combination with an adjuvant.
Claim 59 is drawn to a vaccine composition comprising the vector of claim 41, optionally in combination with an adjuvant.
The specification discloses that the inventors have found that transferring certain mouse IgG3 (mIgG3) Fc residues into the human IgG1 (hIgG1) Fc region of an antigen-Fc fusion protein improves the immunogenicity of the antigen (see page 5, lines 1 and 2). The specification discloses of several COVID-19 plasmids, wherein the backbone for all of these plasmids (pVAXDCSN1-SN14 (SN1-15)) are derived from the FDA regulatory compliant vector backbone of pVAX1 for use in humans (see page 62). All nucleotide sections for insertion were codon optimized for expression in humans; SN1-4 contain a murine IgK leader while SN5-15 contain a human IgH leader (see page 62). Additionally, the specification discloses that ImmunoBody vectors pVAXDCIB8 (SCIB1), pVAXDCIB238 (SCIB1plus), and pVAXDCIB178 (SCIB2) were enhanced by replacing the huIgG1 constant region of the antibody heavy chain encoding the CH1-Hinge-CH2-CH3 domains with the same section encoding the replaced 23 murine IgG3 residues at the specific sites (see page 63; Examples 11-15). The specification discloses that the enhanced SCIB1 (iSCIB1) and enhanced SCIB1plus (iSCIB1) DNA immunizations generated higher avidity TRP2 180-188 specific CD8 responses than SCIB1 DNA immunization in C57BI/6 and HLA-DR4 mice (see Examples 11 and 12; Figures 35B and C). Further, Example 13 teaches that iSCIB1, SCIB1plus, and iSCIB1plus DNA immunization showed significantly enhanced overall survival in mice models with melanoma cells compared to the control (see Figure 36C). Additionally, the specification discloses that the enhanced SCIB2 (iSCIB2) generated higher avidity than SCIB2 in HHDII/DR1 mice (see Example 14; Figures 37B and C). The specification discloses that the in a mouse study with melanoma cells, immunization with both SCIB2 and iSCIB2 demonstrated significantly enhanced tumor free survival over the control mice with no significant difference between the two (see Example 15; Figure 38).
The specification also teaches that targeting antigens to the high affinity CD64 induces better humoral and T cell responses through a combination of enhanced antigen internalization as well as improved APC activation (see Example 20). Further, the specification teaches of a trastuzumab construct containing the modified Fc (iTv1) which generated a small increase in proliferation in 3/20 donors compared to wildtype Trastuzumab and Bydureon® controls, and is unlikely to stimulate potent CD4 T cell responses in humans (see Examples 21 and 22).
However, the specification fails to disclose that Applicant was in possession of the claimed invention. Specifically, the specification fails to disclose that Applicant was in possession of a nucleic acid encoding a polypeptide comprising a large genus of modified Fc regions of a human IgG1 and heterologous antigens as claimed. Further, the specification fails to disclose that Applicant was in possession of an Fc region comprising one modification in at least one residue and that said modification could be anything (e.g., substitution, addition, deletion) as recited in claim 5. Furthermore, the specification fails to disclose that Applicant was in possession of the genus of Fc regions comprising at least 90% identity to SEQ ID NO: 1, nor does the specification teach which sequences must be conserved in order to maintain its function.
Although the specification discloses of iSCIB1, iSCIB2, iSCIB1plus, and iTv1, the claims are not limited to these constructs, and are inclusive of any nucleic acid which encodes a polypeptide comprising: (i) a modified Fc region of a human IgG1, and(ii) at least one heterologous antigen, wherein (a) the modified Fc region comprises at least the part of Fc that is capable of binding to CD64 and/or TRIM21, (b) at least one residue of the Fc region is modified to the corresponding residue from a mouse IgG3 antibody and (c) the modified Fc region has enhanced avidity for Fc- gamma receptor (FcyR) when compared to the corresponding wildtype Fc region. This indicates that there are hundreds, if not thousands, of possible nucleic acid constructs encompassed by the claims. Thus, the claims encompass a vast genus of constructs that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of nucleic acid constructs because, inter alia, the specification does not disclose a correlation between the necessary structure of the Fc region and heterologous antigen of the construct and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Although the term polypeptide does impart some structure, the structure that is common to polypeptides is generally unrelated to its specific binding function; therefore, correlation is less likely for polypeptides than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of polypeptides, even one of skill in the art cannot envision the structure of a polypeptide by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of nucleic acid constructs and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of polypeptides has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of nucleic acid constructs. The disclosure of only one or two 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; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the modified Fc region or heterologous antigen to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of nucleic acid constructs, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous nucleic acid constructs had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of nucleic acid constructs claimed only by a partial structure and functional characteristic(s). Thus the nucleic acid constructs described by the instant claims encompasses an overly broad genus, the structure of the modified Fc region or heterologous antigen, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that 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.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of modified Fc regions by the functions (a) of the modified Fc region comprises at least the part of Fc that is capable of binding to CD64 and/or TRIM21, (b) at least one residue of the Fc region is modified to the corresponding residue from a mouse IgG3 antibody and (c) the modified Fc region has enhanced avidity for Fc- gamma receptor (FcyR) when compared to the corresponding wildtype Fc region. Additionally, the claims attempt to define the genus of heterologous antigens by the vast functions recited in claim 10. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed nucleic acid constructs, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed antibody variable region, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibody variable regions that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibody variable regions or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed polypeptides encoded by the nucleic acids could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Regarding the nucleic acid-based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75–86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three-dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al. (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13).
Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA or polypeptides, an 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 (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all nucleic acid constructs.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed nucleic acid constructs. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of nucleic acids as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 3, 5, 8-10, 14, 28, 35, 41, 51, and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Durrant et al (WO2008/116937 A2; publication date: 10/02/2008; previously submitted with the Restriction Requirement mailed 11/19/2025) and further in view of Davis et al (WO 2010/151792 A1; publication date: 12/29/2010, submitted in IDS filed 01/16/2026) and Allan et al (WO 2007/005612 A2; publication date: 01/11/2007, submitted in IDS filed 01/16/2026).
With respect to instant claims 3, 8-10, 14, 28, and 35, Durrant et al provide a nucleic acid which comprises a non-specific promoter and at least one sequence that encodes a polypeptide that has at least one heterologous T cell epitope therein but does not have any regulatory T cell epitopes (see Abstract). The polypeptide may be one chain of a heterodimer, the heterologous T cell epitope causing disruption of the heterodimer chain such that it cannot bind with the other chain of the heterodimer (see Abstract). The nucleic acid can be used to raise a T cell response against the at least one heterologous T cell epitope (see Abstract). Durrant et al disclose that the CDRs of the heavy and/or light chain of the polypeptide have been substituted by T-cell epitopes (see page 15). Durrant et al also disclose that the epitopes may be cancer or pathogen epitopes (see pages 16 and 17). Durrant et al disclose that the heterologous antigen is linked to the Fc region (see Example 12; Figures 8, 9, and 49). Specifically, Durrant et al disclose of an immunobody wherein CDRH2 comprises the TRP2 epitope SVYDFFVWL (i.e., instant SEQ ID NO: 30). Further, Durrant et al disclose of a double expression vector DCIB63 containing HLA-DR7 restricted gp100 CD4 epitope (GTGRAMLGTHTMEVTVYH; i.e., instant SEQ ID NO: 29) in H1, the TRP2 epitope (SVYDFFVWL) in H2 and the HLA-DR4 restricted gp100 CD4 epitope in H3 (WNRQLYPEWTEAQRLD; i.e., instant SEQ ID NO: 31) (see page 32; Figure 17).
With respect to instant claims 41 and 42, Durrant et al teaches that in order to obtain expression of the nucleic acid sequences the sequences can be incorporated into a vector having one or more control sequences operably linked to the nucleic acid to control its expression (see page 20).
With respect to instant claims 51 and 59, Durrant et al teaches that the nucleic acid of the invention can be made into a vaccine comprising the nucleic acid and an adjuvant (see page 10).
Durrant et al disclose that the claimed polypeptides may be mouse IgG3 (see pages 12 and 13). Additionally, Figures 15 and 16 show sequences comprising substitutions wherein the polypeptide has high affinity interaction with FcyR1 (CD64) (see page 31).
However, Durrant et al fails to disclose of the modifications recited in instant claim 5. This is remedied by Davis and Allan.
Davis teaches Fc-containing proteins with modifications in immunoglobulin domains where the modifications affect one or more effector function of the protein ([0065]) These residues and modifications include D356E and L358M ([0026] and claim 20).
Allan teaches residues and modifications in the Fc region including A339, ,Q342R, R344 to any uncharged residue (e.g., Q but generally not P or C), E345 to any uncharged residue (e.g., Q but generally not P or C), E357 to any uncharged residue (e.g., Q but generally not P or C), T359, N361K, Q362K and K370 to any uncharged residue (e.g., Q but generally not P or C) ([0102], [0103] and claim 69).
As such, one of ordinary skill in the art would have been motivated to combine the teachings of Durrant, Davis, and Allan because Durrant teaches of a nucleic acid which comprises a non-specific promoter and at least one sequence that encodes a polypeptide that has at least one heterologous T cell epitope therein but does not have any regulatory T cell epitopes (see Abstract). Further, Durrant teaches of substitutions wherein the polypeptide has high affinity interaction with FcyR1 (CD64) (see Figures 15 and 16). Additionally, Davis and Allan each teach several specific Fc region modifications that improve or change the properties of the Fc region (improving effector functions or other therapeutic properties). Thus, it would have been obvious to test the modifications of Davis and Allan when introduced into an IgG1 antibody Fc region for the oligomerization properties and the improved functional affinity with a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
12,595,313 (17/631,078)
Claims 3, 5, and 6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8-16, and 19-23 of copending Application No. 17/631,078 (U.S. Patent No. 12,595,313; not published at the time of this action). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to instant claims 3, 5, and 6, the ‘078 application is drawn to a modified IgG1 antibody or antigen-binding fragment thereof comprising residues of an Fc-region of an immunoglobulin and a binding region, wherein residues of the Fc-region comprise N286, K288, K290, Q342, P343, E345, L351, T359, N361, Q362, G371, P374, S375, D376, and A378, numbered according to the IMGT system for the numbering of antibody sequences, are modified to the corresponding residue from a mouse IgG3 antibody, and wherein the modified IgG1 antibody or antigen-binding fragment thereof has enhanced avidity when compared to a corresponding IgG1 antibody or antigen-binding fragment thereof comprising wildtype Fc-region residues (see claims 1-4 and 8-14).
The difference between the instant claims and the ‘078 application is that the ‘078 application is drawn to methods of using the claimed product. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘078 application anticipates the present application.
8,742,088
Claims 3, 5, 8-10, 14, 28, 35, 41, 51, and 59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-51 of U.S. Patent No. 8,742,088B2 (patent date: 06/03/2014) in view of Durrant et al (WO2008/116937 A2; publication date: 10/02/2008; previously submitted with the Restriction Requirement mailed 11/19/2025), Davis et al (WO 2010/151792 A1; publication date: 12/29/2010, submitted in IDS filed 01/16/2026) and Allan et al (WO 2007/005612 A2; publication date: 01/11/2007, submitted in IDS filed 01/16/2026).
With respect to instant claims 3, 5, 8-10, 14, 41-42, 51, and 59, the ‘088 patent is drawn to a nucleic acid which comprises a non-specific promoter and at least one sequence that encodes a recombinant heavy chain of an antibody, wherein the heavy chain has at least one heterologous T cell epitope therein such that the heavy chain does not fold correctly when the nucleic is expressed; wherein the heavy chain stimulates a T cell response against the at least one heterologous T cell epitope; wherein the T cell response is not mediated via CD64; and wherein the heavy chain cannot associate with a light chain to form an intact antibody or associates with a light chain to form decreased amounts of intact antibody as compared to a normal control antibody (see claims 1-51). The ‘088 patent is drawn to a nucleic acid as claimed, wherein the sequence encoding the at least one T cell epitope is inserted into the sequence encoding the variable region of the heavy chain (see claims 9 and 36). The ‘088 patent is drawn to a vaccine comprising a nucleic acid as claimed and an adjuvant (see claims 14 and 50). The ‘088 patent is drawn to a nucleic acid as claimed, wherein the heterologous T cell epitopes are: GTGRAMLGTHTMEVTVYH (SEQ ID NO: 3) in CDRH1 and CDRL3; SVYDFFVWL (SEQ ID NO: 9) in CDRH2; and WNRQLYPEWTEAQRLD (SEQ ID NO: 15) in CDRH3 and CDRL1 (see claims 17 and 48).
The ‘088 patent fails to disclose of a nucleic acid encoding a polypeptide comprising a modified Fc region of a human IgG1. However, Durrant et al provide a nucleic acid which comprises a non-specific promoter and at least one sequence that encodes a polypeptide that has at least one heterologous T cell epitope therein but does not have any regulatory T cell epitopes (see Abstract). The polypeptide may be one chain of a heterodimer, the heterologous T cell epitope causing disruption of the heterodimer chain such that it cannot bind with the other chain of the heterodimer (see Abstract). The nucleic acid can be used to raise a T cell response against the at least one heterologous T cell epitope (see Abstract). Durrant et al disclose that the CDRs of the heavy and/or light chain of the polypeptide have been substituted by T-cell epitopes (see page 15). Durrant et al also disclose that the epitopes may be cancer or pathogen epitopes (see pages 16 and 17). Durrant et al disclose that the heterologous antigen is linked to the Fc region (see Example 12; Figures 8, 9, and 49). Specifically, Durrant et al disclose of an immunobody wherein CDRH2 comprises the TRP2 epitope SVYDFFVWL (i.e., instant SEQ ID NO: 30). Further, Durrant et al disclose of a double expression vector DCIB63 containing HLA-DR7 restricted gp100 CD4 epitope (GTGRAMLGTHTMEVTVYH; i.e., instant SEQ ID NO: 29) in H1, the TRP2 epitope (SVYDFFVWL) in H2 and the HLA-DR4 restricted gp100 CD4 epitope in H3 (WNRQLYPEWTEAQRLD; i.e., instant SEQ ID NO: 31) (see page 32; Figure 17). Durrant et al teaches that in order to obtain expression of the nucleic acid sequences the sequences can be incorporated into a vector having one or more control sequences operably linked to the nucleic acid to control its expression (see page 20). Durrant et al teaches that the nucleic acid of the invention can be made into a vaccine comprising the nucleic acid and an adjuvant (see page 10).
Durrant et al disclose that the claimed polypeptides may be mouse IgG3 (see pages 12 and 13). Additionally, Figures 15 and 16 show sequences comprising substitutions wherein the polypeptide has high affinity interaction with FcyR1 (CD64) (see page 31). However, Durrant et al fails to disclose of the modifications recited in instant claim 5. This is remedied by Davis and Allan.
Davis teaches Fc-containing proteins with modifications in immunoglobulin domains where the modifications affect one or more effector function of the protein ([0065]) These residues and modifications include D356E and L358M ([0026] and claim 20). Additionally, Allan teaches residues and modifications in the Fc region including A339, ,Q342R, R344 to any uncharged residue (e.g., Q but generally not P or C), E345 to any uncharged residue (e.g., Q but generally not P or C), E357 to any uncharged residue (e.g., Q but generally not P or C), T359, N361K, Q362K and K370 to any uncharged residue (e.g., Q but generally not P or C) ([0102], [0103] and claim 69).
As such, one of ordinary skill in the art would have been motivated to combine the teachings of the ‘088 patent, Durrant, Davis, and Allan because the ‘088 patent and Durrant teach of a nucleic acid which comprises a non-specific promoter and at least one sequence that encodes a polypeptide that has at least one heterologous T cell epitope therein but does not have any regulatory T cell epitopes (see Abstract). Further, Durrant teaches of substitutions wherein the polypeptide has high affinity interaction with FcyR1 (CD64) (see Figures 15 and 16). Additionally, Davis and Allan each teach several specific Fc region modifications that improve or change the properties of the Fc region (improving effector functions or other therapeutic properties). Thus, it would have been obvious to test the modifications of Davis and Allan when introduced into an IgG1 antibody Fc region for the oligomerization properties and the improved functional affinity with a reasonable expectation of success.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Vankemmelbeke et al (Cancer Res. 2020 August 15; 80(16): 3399–3412) disclose of engineering the human Fc-region enables direct cell killing by cancer glycan-targeting antibodies without the need for immune effector cells or complement comprising transferring mIgG3 CH2 and CH3 residues into the hIgG1 isotype.
Pudney et al (Eur. J. Immunol. 2010. 40: 899–910) disclose of DNA vaccination with T-cell epitopes encoded within Ab molecules induces high-avidity anti-tumor CD8+ T cells.
Brentville et al (PLoS ONE 7(7): e41112 (2012)) disclose of high avidity cytotoxic T lymphocytes can be selected into the memory pool but are exquisitely sensitive to functional impairment.
Patel et al (ONCOIMMUNOLOGY, 2018, VOL. 7, NO. 6, e1433516) disclose of targeting gp100 and TRP-2 with a DNA vaccine: incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favorable clinical outcome in a phase I/II trial.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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