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 .
Response to Amendment
The amendment filed 8 May 2026 is acknowledged. Claim 14 is amended . Claim 16 is cancelled.
Claim Status
Claims 1, 3-14, and 17-21 are pending. Claims 1, 3-13 and 21 are withdrawn as previously described. Claims 14 and 17-20 are under examination in the instant office action.
Withdrawal of Rejections
The rejection of claims 14 and 18-20 under 35 U.S.C. 102(a)(1) as being anticipated by WO2016106158 A1 to Gao et. al. published 30 June 2016 as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 is withdrawn in view of the amendment to the claims.
The rejection of claim 17 under 35 U.S.C. 103 as being unpatentable over WO2016106158 A1 to Gao et. al. published 30 June 2016 as applied to claim 14 above, and further in view of Kim et. al. “Gene Therapy using plasmid DNA-encoded anti-HER2 antibody for cancers that overexpress HER2,” , published September 16, 2016 (Of record, PTO-892 dated 6/13/2025) is withdrawn in view of the amendment to the claims.
The
Claim Rejections - 35 USC § 112(b)- New, necessitated by amendment
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 14 and 17-20 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 14 is indefinite for the language of parts b) and d) reciting “a fragment of a nucleotide sequence having at least 95% identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, and SEQ ID NO:65, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and wherein the fragment comprises at least 65% of the full length nucleotide sequence” and “a fragment of a nucleotide sequence selected from the group consisting of SEQ ID NO: 61 and SEQ ID NO: 63, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and comprises at least 65% of the full length nucleotide sequence”. The language is not clear because it is unsure whether the “fragment of a nucleotide sequence” is selected from the group or whether the fragment is a fragment of a full-length nucleotide sequence wherein the full-length nucleotide sequence is chosen from the group. It is not understood whether it is the fragment or the full length nucleotide sequence has at least 95% identity to the recited sequence identifiers. Additionally, a sequence having 95% identity to the full length of e.g. SEQ ID NO: 65 must naturally comprise 65% of the full length nucleotide sequence; and if the 65% fragment is non-continuous, it is not clear what portions of the nucleotide sequence are required to be 95% identical. As an additional example, it is unclear whether a nucleotide sequence comprising at least 449/724 amino acids of SEQ ID NO: 65 would fall into the scope of the current claims if it does not have a continuous segment comprising the VH and VL that is 95% identical to SEQ ID NO: 65. The Examiner requests amendment of the claim to clarify which limitations apply to the fragment as compared to the full-length nucleotide sequence and to specifically define which fragments are encompassed by the metes and bounds of the claim. Regarding part b), the limitations as claimed were not further examined due to lack of clarity. For the purposes of expedited prosecution, part b) is interpreted to mean a fragment of a full-length nucleotide sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 63, and SEQ ID NO: 65, wherein the fragment comprises at least 62% (95% x 65%) of the full length nucleotide sequence.
Claim Rejections - 35 USC § 112(a)- Maintained, modifications necessitated by amendment
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 14 and 17-20 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.
Regarding claim 14, options a) a nucleotide sequence having at least 95% identity over an entire length of the nucleic acid sequence to a nucleotide sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 63, an SEQ ID NO: 65; b) a fragment of a nucleotide sequence having at least 95% identity to a nucleotide sequence selected from the group consisting of SEQ ID NO: 61, 63, and 65, wherein the fragment comprises at least 65% of the full length nucleotide sequence; and d) a fragment of a nucleotide sequence selected from the group consisting of SEQ ID NO: 61 and SEQ ID NO: 63, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and comprises at least 65% of the full length nucleotide sequence, but the art and genus of known species does not allow for predictable binding of the recited function of binding HER2.
Scope of the claimed genus
The instant claims are directed towards a nucleic acid molecule encoding one or more synthetic antibodies, wherein the nucleic acid molecule comprises at least one selected from the group consisting of:
a) a nucleotide sequence having at least 95% identity over an entire length of the nucleic acid sequence to a nucleotide sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, and SEQ ID NO:65; b) a fragment of a nucleotide sequence having at least 95% identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, and SEQ ID NO:65, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and wherein the fragment comprises at least 65% of the full length nucleotide sequence; c) a nucleotide sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, and SEQ ID NO:65; and d) a fragment of a nucleotide sequence selected from the group consisting of SEQ ID NO:61, and SEQ ID NO:63, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and wherein the fragment comprises at least 65% of the full length nucleotide sequence
Regarding fragments, the examiner notes that the instant specification defines “fragment” as follows:
"Antibody fragment" or "fragment of an antibody" as used interchangeably herein refers to a portion of an intact antibody comprising the antigen-binding site or variable
region. The portion does not include the constant heavy chain domains (i.e. CH2, CH3, or CH4, depending on the antibody isotype) of the Fc region of the intact antibody. (p. 11 lines 17-26).
Regarding fragments of nucleic acid sequences, the specification does not offer a closed definition of a fragment of a nucleic acid, but suggests the fragment may comprise as little as 20% of the length of the full length coding sequence (p. 13 line 28- p. 14 line 10).
Therefore, the broadest reasonable interpretation of the “fragment of a nucleotide sequence having at least 95% identity to a nucleotide sequence selected from the group consisting of SEQ ID NO:61, SEQ ID NO:63, and SEQ ID NO:65, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and wherein the fragment comprises at least 65% of the full length nucleotide sequence” and the “a fragment of a nucleotide sequence selected from the group consisting of SEQ ID NO:61, and SEQ ID NO:63, wherein the fragment encodes at least a VH and a VL domain of the synthetic antibody and wherein the fragment comprises at least 65% of the full length nucleotide sequence” is that the claim requires at least 65% (e.g. 472 nucleotides of elected SEQ ID NO: 65) (that are at least 95% identical or 100% identical, respectively) and that SEQ ID NOs 61, 63, and 65 recite the “full-length” sequences from which there is a fragment. However, the examiner notes that the claim only requires that the sequences encode an antibody that binds HER2; there is no language in the claims that requires that antibody to have the same anti-HER2 binding domain as the antibodies encoded by SEQ ID NOs: 61, 63, or 65.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1) (PTO-892 1/8/2026). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80; PTO-892 1/8/2026) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “95% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. Further, 95% identity over a fragment at least 65% of the nucleic acid sequence is indefinite, but appears to allow for fragments that lack complete CDR regions and does not allow an artisan to envisage those fragments of nucleic acids or encoding amino acid fragments that would sufficiently retain HER2 binding.
Additionally, 95% identity to SEQ ID NO: 61, 63, or 65, or to fragments encode an anti-HER2 antibody VH and VL and 65% of the length of SEQ ID NOs: 61, 63, or 65 allows for significant changes to the CDRs in both the VH and the VL of the antibody:
For example, 65% of the length of SEQ ID NO: 61 encompasses 1424 nt, which encodes approximately 475 amino acids out of 728 in the polypeptide SEQ ID NO: 62 for which SEQ ID NO: 61 encodes. Because the heavy and light chain the HER2 binding domain of SEQ ID NO: 62 both less than 475 nt long, this means that the nucleotide fragment may comprise only a partial VL nucleotide sequence of SEQ ID NO: 61 or VH nucleotide sequence, allowing for complete exchange of one or the other (the VH and VL are highlight in light grey; a fragment comprising 1424/2190 nt is underlined to show that the 65% of the length of SEQ ID NO: 61 does nt require any particular structure or sequence of one of the VH or the VL):
atggattggacatggattctgtttctggtcgccgccgccacaagagtgcattccgaagtgcagctggtcgagtcagggggaggactggtgcagcccggcggaagcctgcgactgtcctgcgccgcttctggcttcacttttaccgactacaccatggattgggtgcgccaggcacctgggaagggactggaatgggtcgctgatgtgaacccaaatagtgggggctcaatctacaaccagcgattcaaaggcaggtttaccctgagtgtggacagatcaaagaacacactgtatctgcagatgaatagcctgagggcagaggataccgccgtgtactattgcgccagaaatctgggaccatccttctactttgactattggggacaggggactctggtcaccgtgagctccgcctcaacaaaaggccccagcgtgttccccctggctccttctagtaagtctacaagtggagggactgcagccctgggatgtctggtgaaggactacttccctgagccagtcaccgtgagctggaactccggcgctctgacttctggagtccacacctttcccgcagtgctgcagtcaagcgggctgtactccctgtcctctgtggtcaccgtccctagttcaagcctgggcacacagacttatatctgcaacgtgaatcacaaaccatctaatacaaaggtcgacaagaaagtggaacccaaaagctgtgataagacccatacatgccctccctgtccagctcctgagctgctgggcggaccaagcgtgttcctgtttccacccaagcctaaagataccctgatgatttcccggaccccagaagtcacatgcgtggtcgtggacgtgtctcacgaggaccccgaagtcaagtttaactggtacgtggacggcgtcgaggtgcataatgccaagacaaaaccacgcgaggaacagtacaactccacttatcgagtcgtgtctgtcctgaccgtgctgcatcaggattggctgaacgggaaggagtataagtgcaaagtgagcaacaaggccctgccagctcccatcgagaagaccatttccaaggcaaaaggccagccacgggaaccccaggtgtacacactgcctccatctcgcgatgagctgaccaaaaaccaggtcagtctgacatgtctggtgaagggcttctatccctcagacatcgccgtggagtgggaatccaatggacagcctgaaaacaattacaagaccacaccccctgtgctggactctgatggaagtttctttctgtatagtaaactgactgtggataagtcaaggtggcagcaggggaacgtcttttcatgcagcgtgatgcacgaggccctgcacaatcattacacacagaaatccctgtctctgagtcctggaaaacgggggcgcaagaggagatcaggcagcggagcaacaaacttcagcctgctgaagcaggcaggggacgtggaggaaaatcctggcccaatggattggacttggattctgttcctggtcgctgcagccactagggtgcatagcgacattcagatgacccagtccccctcctctctgtccgcctctgtcggcgacagagtgactatcacctgtaaggctagccaggatgtctccattggagtggcatggtaccagcagaagcctgggaaagctccaaagctgctgatctacagtgcatcatacagatatacaggagtgccttcccggttcagcgggtccggctctggaactgactttacactgactatcagttcactgcagcctgaggatttcgctacctactattgccagcagtactatatctacccatatacatttgggcagggcactaaagtggaaatcaagcggactgtcgctgcacctagcgtgttcatctttccacccagtgatgagcagctgaagtctggaaccgccagtgtggtgtgcctgctgaacaatttctacccacgcgaagccaaagtccagtggaaggtggacaacgctctgcagtcagggaatagccaggagtccgtgacagaacaggactctaaagatagtacttattcactgagctccaccctgacactgtccaaggcagactacgagaagcacaaagtgtatgcctgcgaggtcactcaccaggggctgtcttcacccgtcactaagtcctttaatagaggggaatgttgataa
Therefore, a person of ordinary skill in the art would not be able to determine a priori from a sequence at least 95% identical to a fragment 65% of the full length of SEQ ID NO: 61 whether it bound to HER2 from the instant specification. Additionally, the claims encompass nucleic acids encoding potential anti-HER2 antibodies with CDRs that have yet to be invented.
In regards to anti-HER2 antibodies, other anti-HER2 antigen binding sites are known in the art. For example, US 20110256056 to Alper teaches anti-HER2 monoclonal antibodies (abstract), in particular a heavy chain SEQ ID NO: 1 and light chain SEQ ID NO: 5, which are 51.8% and 61.3% identical to the VH and VL of instant SEQ ID NO: 64 with different CDRs:
Instant SEQ ID NO: 64 compared to VH SEQ ID NO: 1 of Alper
RESULT 1
AASEQ2_12192025_194340
Query Match 7.2%; Score 278.5; DB 1; Length 106;
Best Local Similarity 51.8%;
Matches 57; Conservative 14; Mismatches 34; Indels 5; Gaps 3;
Qy 26 GGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGR 85
| || | || ::| |||: | | : |||| |||||||: | ||: || | |
Db 1 GPGLAAPSQSLSITCTVSGFSLTSYVISWVRQPPGKGLEWLG-VIWTGGGTNYNSALKSR 59
Qy 86 FTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSF-YFDYWGQGTLVT 134
::| | ||: : |:||||: :||| |||| |: |||||||| ||
Db 60 LSISKDNSKSQVSLKMNSLQTDDTARYYCA---SLSYDGFDYWGQGTTVT 106
Instant SEQ ID NO: 64 compared to VH SEQ ID NO: 5 of Alper
RESULT 1
AASEQ2_12192025_194716
Query Match 8.4%; Score 324.5; DB 1; Length 105;
Best Local Similarity 61.3%;
Matches 65; Conservative 15; Mismatches 25; Indels 1; Gaps 1;
Qy 516 IQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSR 575
| |||||: :||| |::||:|| || || : ||||| | :|| || | :|||:|
Db 1 ILMTQSPAIMSASPGEKVTMTCSASSSVSY-MHWYQQKSGTSPKRWIYDTSKLASGVPAR 59
Qy 576 FSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIK 621
|||||||| ::|||||:: || |||||||: | ||| |||:|||
Db 60 FSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLEIK 105
As an additional example, up to 4 amino acids residues changed in the CDRs can result in an antigen binding domain specific for an entirely different antigen target. U.S. Patent No. 11584790 teaches a light chain for an antibody VL of SEQ ID NO: 456 which has only 4 residue changes from VL of instant SEQ ID NO: 64, but the antibody is specific for complement factor D (CFD)(Table 1.1 Col. 116).
Query Match 63.1%; Score 88.3; Length 107;
Best Local Similarity 31.1%;
Matches 23; Conservative 1; Mismatches 3; Indels 47; Gaps 2;
Qy 1 KASQDVSIGVA---------------SASYRYT--------------------------- 18
||||||| || |||||||
Db 24 KASQDVSNAVAWYQLKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAADL 83
Qy 19 -----QQYYIYPYT 27
||:|| |||
Db 84 AVYYCQQHYITPYT 97
Thus, it would not be apparent a priori which nucleic acid sequences with only partial identity to the instant CDRs would bind to HER2 as claimed.
Instant SEQ ID NOs: 62, 64, and 66 are amino acid sequences of the conventional anti-HER2 therapeutic antibody pertuzumab. Franklin, Matthew C., et al. "Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex." Cancer cell 5.4 (2004): 317-328 (PTO-892 1/8/2026) teaches:
The interface between ErbB2 and pertuzumab is primarily polar, with few hydrophobic or charged residues in the interface. The largest hydrophobic patch lies outside the main CDR surface, between Ile 58 and Tyr 59 (heavy chain), Tyr 94 (light chain), and Tyr 252 and Phe 257 (ErbB2). (For consistency with previous work on the pertuzumab Fab [Vajdos et al., 2002], we have chosen to use a modified Kabat numbering rather than sequential numbering for pertuzumab residues.) Residues 30–32 on CDR H1 and 52–53 on CDR H2 make an extensive network of hydrogen bonds with main chain and side chain atoms (Figure 2B). His 245 of ErbB2 is tightly sandwiched between Ile 244 and Gly 55 of CDR H2. Although not technically a CDR, the loop containing residues 72–76 makes contacts with ErbB2, including the only contact with domain I, a hydrogen bond between Lys 75 of pertuzumab and Gln 156 of ErbB2. Finally, CDR H3 makes hydrophobic and hydrogen bond contacts with residues Lys 311 and His 296 of ErbB2. His 296 is thoroughly buried upon pertuzumab binding, being surrounded by Tyr 49 and Tyr 55 of the light chain, and Leu 96 and Tyr 99B (modified Kabat numbering) of the heavy chain (Figure 2C). (p. 321 left column)
Franklin et. al. further teaches contacting residues P98, L96, Y55, Y49, and Y53 in the H-CDR3 and L-CDR2. However, Franklin further teaches “Conversely, light-chain residues which do affect binding when mutated do so indirectly, since none of these residues contacts ErbB2 (Figure 5B). The picture is quite different for the pertuzumab heavy chain, where 24 residues contact ErbB2 directly; seven of these affect binding by at least 75-fold when mutated (Figure 5B)” (p. 323 left column, ¶3). Nonetheless, the art does not allow accurate prediction of paratope/epitope binding even for conventional antibodies with known crystal structures indicating the contacting residues. As indicated by Franklin et. al., the non-contacting residues can also be essential for antigen binding. Dondelinger M, et. al., Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278 (PTO-892 1/8/2026) teaches “it should be noted that: (i) some contacting residues may contribute minimally to the binding free energy and even disfavor the complex formation and; (ii) that a residue energetically important for binding to the cognate antigen may not be important for the difference in affinity between cognate and non-cognate antigens and, finally; (iii) a residue crucial for antigen recognition may not be important for binding free energy” (p. 8, right column).
Sela-Culang et al. teaches contacting residues are more common at CDRs residues which are located at the center of the Ag combining site, and that non-contacting residues within the CDRs correspond with residues that are important for maintaining the structural conformations of the hypervariable loops and not necessarily for recognition of the Ag (Sela-Culang I, et. al. The structural basis of antibody-antigen recognition. Front Immunol. 2013 Oct 8;4:302; PTO-892 1/8/2026). Thus, without mutating the individual epitope-interacting amino acids and the surrounding amino acids within the CDR and testing the binding, it is unknown how the epitope will interact with the CDR. The claimed CDR would allow for vast changes to the CDR charge, polarity, and side chain size as well as conformational constraints when proline residues are substituted.
Summary of Species disclosed in the original specification
The instant specification discloses 3 species of nucleic acid encoding amino acid sequences of SEQ ID NOs: 62, 64, and 66; in particular, the three nucleic acid sequences SEQ ID NOs: 61, 63, and 65. All of SEQ ID NOs: 62, 64, and 66 comprise identical VH and VL sequences. There are no alternate CDR residues or alternate framework residues disclosed.
Do the disclosed species represent a genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Because only three species are identified and the state of the art, described above, would not allow an artisan to at once envision all of the nucleic acids encoding a HER2-specific antibody comprising 98% identity to SEQ ID NOs: 62, 64, or 66, three species cannot be considered representative of a genus. One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of nucleic acids encoding antibodies to allow complete exchange of the CDR residues as claimed.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
In the instant application, there is no structure/function relationship described apart from the particular VH and VL of SEQ ID NOs: 62, 64, 66 (which is the same VH and VL of the conventional antibody pertuzumab) encoded by SEQ ID NOs: 61, 63, and 65. As described in the state of the art section above, an artisan would not be able to discern from only the pertuzumab VH and VL, which have 6 complete CDRs encoding a complete antigen binding domain, whether the nucleic acid with only partial identity to the CDRs as claimed performs the claimed function of encoding the antibody of claim 14.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein HER2, and therefore for the nucleotide sequences encoding the CDR residues of the antibody. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polynucleotide of claim 14 at the time of filing. Regarding claims 17-20 the claims are ultimately dependent on the rejected claim 14 without narrowing the claimed subject matter and thus are also rejected.
Response to Arguments
The Remarks filed 5/8/2026 have been fully considered but are not persuasive. Applicant argues that the instant claims are directed to a genus of sequences encoding anti-HER2 synthetic antibodies comprising variants and fragments of SEQ ID NOs: 61, 63, and 65, which are fully supported by the specification as-filed and that a person of skill in the art, provided with the description of the HER2 antibody structure as detailed in the Specification and knowledge of the art would understand the inventors to have possession of the claimed subject matter (Remarks 5/8/2026 p. 9-10). The Examiner disagrees. As described in the written description rejection above, the instant claims are not directed, as suggested by Applicant, at a genus of nucleotides encoding the HER2 antibody structure described in the specification. Rather, the instant claims are directed towards a broad genus of nucleotides encoding anti-HER2 antibodies comprising only fragments and partial identity to the instantly claimed sequences limited only by function.
Applicant argues that as claimed, the instant claims draw a clear structure/function correlation and that the requirement of “the full VH and VL domains which ensures the complete antigen-binding domain is present regardless of the physical distance between these domains in the parent sequence” along with the functional requirements that the claims are now directed towards the described genus (Remarks 5/8/2026 p. 10, bottom paragraph). This is not persuasive because, as described in the written description rejection above, the instant antibodies are required to have a complete binding site comprising a VH and VL domain, but there is no requirement that the VH and VL domain as claimed comprise =the nucleotides encoding any of the CDR residues of the antibodies described in the specification. The claims therefore are still directed towards a genus of nucleotides encoding HER2 antibodies, including with light chain or heavy chain CDRs that have yet to be invented.
The Examiner suggests amending claim 14 to require that the nucleotide encode at least the entire binding-determinant region of the instantly described antibody by reciting that the encoded anti-HER2 antibody must comprise at least the 6 CDRs of SEQ ID NO: 66 or the complete VH/VL domains within SEQ ID NO: 66.
Claim Rejections - 35 USC § 102- Maintained, changes necessitated by amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 14 and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2016106158 A1 to Gao et. al. published 30 June 2016 (PTO-892 1/8/2026) as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 (PTO-892 1/8/2026).
Claim interpretation: The instant claims are directed towards a nucleic acid molecule encoding one or more anti-HER2 synthetic antibodies. Regarding synthetic antibodies, the instant specification define a synthetic antibody as “an antibody that is encoded by the recombinant nucleic acid sequence described herein and is generated in a subject” (p. 17 lines 27-28). Although this is a closed definition, the Examiner notes that this definition refers to a product-by-process because “is encoded” and “is generated in a subject” are related to methods of generating the antibody. Regarding product-by-process claims, MPEP §2113 states “"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted)”. As applied to the instant definition of “synthetic antibody” there is no additional structure added to the nucleic acid or the synthetic antibody by “is encoded by a recombinant nucleic acid”. The phrase “is generated in a subject” adds structure to the antibody only inasmuch as antibodies generated in cells have post-translational modifications specific to the cell type of a subject (e.g. an antibody generated in a mammalian cell has mammalian post-translational modifications and glycosylation as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217.).
Regarding fragments of nucleic acids, as described in the 112(b) rejection above, the instant specification does not have a closed definition of a fragment of a nucleic acid. For the purposes of expedited prosecution, part b) is interpreted to mean a fragment of a full-length nucleotide sequence selected from the group consisting of SEQ ID NO: 61, SEQ ID NO: 63, and SEQ ID NO: 65, wherein the fragment comprises at least 62% (95% x 65%) of the full length nucleotide sequence.
Gao et. al. teaches a bispecific tetravalent antibody having a binding specificity for HER2 (Abstract). Gao et. al. teaches the anti-HER2 scFv antibody comprising SEQ ID NO: 19 (p. 6 lines 3-8, Table 2 p. 13) which is 100% identical to instant SEQ ID NO: 66:
Query Match 100.0%; Score 1278; Length 241;
Best Local Similarity 100.0%;
Matches 241; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIY 60
Qy 61 NQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSG 120
Qy 121 GGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKL 180
Qy 181 LIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEI 240
Qy 241 K 241
|
Db 241 K 241
Gao et. al. teaches SEQ ID NO: 17 which is a nucleic acid encoding SEQ ID NO: 19 (Table 2 p. 13), which comprises a nucleic acid fragment comprising a nucleic acid sequence encoding the VH and the VL of the anti-HER2 antibody that is 63.5% identical to instant SEQ ID NO: 65:
RESULT 1
NASEQ2_06232026_125245
Query Match 63.5%; Score 461.2; DB 1; Length 1450;
Best Local Similarity 77.4%;
Matches 559; Conservative 0; Mismatches 163; Indels 0; Gaps 0;
Qy 1 GAGGTGCAGCTGGTGGAGTCTGGCGGCGGCCTGGTGCAGCCCGGCGGCTCTCTGAGACTG 60
|| |||||||| || || || ||||| ||||| |||||||| || |||||| | |||
Db 727 GAAGTGCAGCTCGTCGAAAGCGGTGGCGGACTGGTTCAGCCCGGTGGTTCTCTGCGGCTG 786
Qy 61 TCTTGTGCCGCCTCTGGCTTTACCTTCACAGATTATACCATGGATTGGGTGAGACAGGCC 120
|||||||| ||||| || || || ||||| || || || ||||| |||||| | |||||
Db 787 TCTTGTGCTGCCTCGGGTTTCACGTTCACTGACTACACAATGGACTGGGTGCGTCAGGCT 846
Qy 121 CCTGGCAAGGGCCTGGAGTGGGTGGCCGATGTGAACCCCAATAGCGGCGGCTCCATCTAC 180
||||| ||||| |||||||||| ||||| || || || || |||||| |||||||
Db 847 CCTGGAAAGGGATTGGAGTGGGTAGCCGACGTTAATCCAAACTCCGGCGGGAGCATCTAC 906
Qy 181 AATCAGAGGTTTAAGGGCCGCTTTACACTGTCTGTGGACCGGTCTAAGAACACCCTGTAC 240
|| |||||||| ||||| | || || ||| ||||| || || |||||||| ||||||
Db 907 AACCAGAGGTTCAAGGGGAGGTTCACTCTGAGCGTGGATCGCTCCAAGAACACGCTGTAC 966
Qy 241 CTGCAGATGAATTCTCTGAGAGCCGAGGACACCGCCGTGTATTACTGTGCCAGGAATCTG 300
|| |||||||| ||||| || ||||||||||| || || || || || || ||||| |||
Db 967 CTCCAGATGAACTCTCTCAGGGCCGAGGACACGGCTGTTTACTATTGCGCGAGGAACCTG 1026
Qy 301 GGCCCTTCTTTCTATTTCGACTACTGGGGCCAGGGCACACTGGTGACCGTGTCCTCCGGC 360
|| ||||| ||||| |||||||||||||| ||||| || ||||||||||| ||||||
Db 1027 GGTCCTTCCTTCTACTTCGACTACTGGGGACAGGGAACCCTGGTGACCGTCAGCTCCGGT 1086
Qy 361 GGCGGCGGCAGCGGCGGCGGCGGCTCTGGCGGCGGCGGCAGCGACATCCAGATGACCCAG 420
|| ||||| ||||| || || || ||||| |||||| ||||||||||||||| ||
Db 1087 GGAGGCGGTTCAGGCGGAGGTGGTTCCGGCGGTGGCGGCTCCGACATCCAGATGACACAA 1146
Qy 421 TCCCCAAGCTCCCTGTCTGCCTCCGTGGGCGATCGCGTGACCATCACATGCAAGGCCTCC 480
|| || ||| ||| || || || ||||| || |||||||||||||||||| |
Db 1147 TCTCCTAGCAGTCTGAGCGCAAGTGTTGGAGATCGTGTCACCATCACATGCAAGGCCAGC 1206
Qy 481 CAGGACGTGTCTATCGGCGTGGCCTGGTACCAGCAGAAGCCTGGCAAGGCCCCAAAGCTG 540
||||| ||| || || || |||||||| |||||||| || |||||||| || ||||||
Db 1207 CAGGATGTGAGCATTGGAGTCGCCTGGTATCAGCAGAAACCCGGCAAGGCACCCAAGCTG 1266
Qy 541 CTGATCTACTCTGCCTCCTATAGATACACCGGCGTGCCCTCTAGATTCTCCGGCTCTGGC 600
||||||||||| ||| || |||||||| ||||| || || || || || ||
Db 1267 CTGATCTACTCGGCCAGTTACAGATACACTGGCGTACCTTCGAGGTTTAGTGGTAGCGGT 1326
Qy 601 TCTGGCACCGACTTCACACTGACCATCTCTTCTCTGCAGCCCGAGGACTTCGCCACCTAC 660
||||| ||||| ||||| || ||||| || || || |||||||||||||||||||||
Db 1327 TCTGGAACCGATTTCACCCTCACCATTAGCTCCCTCCAACCCGAGGACTTCGCCACCTAC 1386
Qy 661 TATTGTCAGCAGTACTACATCTACCCTTACACCTTCGGACAGGGGACAAAAGTGGAAATC 720
|| || ||||| |||||||||||||||||||| ||||| || || || || || || ||
Db 1387 TACTGCCAGCAATACTACATCTACCCTTACACGTTCGGCCAAGGCACTAAGGTCGAGATT 1446
Qy 721 AA 722
||
Db 1447 AA 1448
Regarding claim 18, Gao et. al. teaches an expression vector comprising the nucleic acid sequence (p. 8 lines 3-10; p. 11 lines 4-6). Gao et. al. teaches a method of producing an antibody comprising a host cell comprising an expression vector encoding the antibody or a fragment or subcomponent thereof, wherein the host cell is prokaryotic cell or a eukaryotic cell (p. 8 lines 3-10). As evidenced by Frenzel et al. “the advanced mammalian folding, secretion and post-translational apparatus is capable of producing antibodies indistinguishable from those in the human body with least concerns for immunogenic modifications” (p. 5 right column, “Mammalian Cells” section ¶1, emphasis is the Examiner’s). An antibody produced by a eukaryotic expression system would have all of the post-translational modifications and glycosylations and therefore would have an identical structure to an antibody produced in a eukaryotic subject.
Regarding claim 19, Gao et. al. teaches a host cell comprising the nucleic acid (p. 8 lines 3-10), which reads on the instant composition comprising the nucleic acid.
Regarding claim 20, Gao et. al. teaches “Transient expression of the antibody constructs was achieved using transfection of suspension-adapted HEK293F cells with linear PEI as described in CSH Protocols; 2008; doi:10.1101/pdb.prot4977” (p. 11 lines 7-13). PEI is a transfection facilitating agent, which is an excipient as described in the instant specification (p. 49 lines 1-9); therefore, Gao et. al. teaches the composition comprising the instant nucleic acid and an excipient.
Claim Rejections - 35 USC § 103- Maintained, changes necessitated by amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over WO2016106158 A1 to Gao et. al. published 30 June 2016 (PTO-892 1/8/2026) as applied to claim 14 above, and further in view of Kim et. al. “Gene Therapy using plasmid DNA-encoded anti-HER2 antibody for cancers that overexpress HER2,” , published September 16, 2016 (Of record, PTO-892 dated 6/13/2025).
The teachings of Gao et. al. in regard to claim 14 are in the 102 rejection above. Gao et. al. does not teach a nucleic acid encoding the instant antibody wherein the nucleotide sequence is operably linked to a nucleic acid sequence encoding an IgE leader sequence.
This deficiency is resolved by Kim et. al.
Kim et. al. teaches the construction of plasmids encoding a recombinant anti-HER2 antibody for tumor gene therapy. Kim et. al. teaches that the expression plasmid coding for the heavy or light chain of parental murine antibody Herceptin with the antibody genes codon and RNA optimized in the pVax1 backbone (Abstract). Kim teaches the genes encoding the heavy or light chain were codon-and RNA-optimized and fused to the Kozak and IgE leader sequences for the purpose of efficient expression in mammalian cells and tissues (page 344, paragraph 2). Kim et. al. teaches that the HER2 dMab expression plasmids were expressed in human muscle RD cells in vitro and that intramuscular injections of the plasmid into mice followed by electroporation resulted in antibody expression in mouse sera (Fig. 3). Kim et. al. teaches “In the present study, we observed that a single intramuscular injection of 100 μg of the expression plasmids exhibited almost the same therapeutic efficacy as that of four intravenous injections of 10 mg kg−1 Herceptin. This result, taken together with the low production costs and simple manufacturing steps involved with plasmid DNA, suggests that dMAbs may be more simple and efficient than antibody protein therapy” (p. 346 left column, ¶3).
It would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was filed to generate a nucleic acid molecule encoding one or more synthetic antibodies, wherein the nucleic acid molecule comprises a nucleotide sequence encoding the anti-HER2 antibody of Gao et. al. and wherein the nucleotide sequence is operably linked to a nucleic acid sequence encoding an IgE leader sequence. One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success given Kim et. al. teaches and demonstrates successfully using an IgE leader sequence linked to their HER2 antibody for translation and production of their HER2 antibody in order to benefit from the anti-tumor efficacy and low production costs and simple manufacturing steps of gene therapy via in vivo antibody expression as taught by Kim et. al. Given the shared and established conventional HER2 antibodies taught by the prior art, one of skill in the art could have substituted the conventional HER2 antibody of Gao et. al. for the trastuzumab-based antibody in the construct of Kim et. al. and produced the plasmid encoding the HER2 antibody with a reasonable expectation of success.
Response to Arguments
The Remarks filed 5/8/2026 have been fully considered but are not persuasive. Applicant argues that the amendment to claim 14 overcomes the rejection based on Gao because “Gao does not teach each and every element of amended claim 14, from which claims 18-20 depend. Specifically, Gao does not teach or suggest a nucleic acid molecule encoding one or more anti-human epidermal growth factor receptor 2 (HER2) synthetic antibodies, wherein the nucleic acid molecule encodes at least one sequence selected from the claimed sequences SEQ ID NOs: 61, 63, and 65, or their recited fragments and variants” (Remarks 5/8/2026 p. ). This is not persuasive because as described in the 112(b) and 102 rejections above, the instantly claimed fragments are indefinite and therefore it is unclear whether the fragment of a nucleic acid sequence SEQ ID NO: 17 taught by Gao reads on the instantly claimed fragments; for the purposes of expedited prosecution, under the interpretation that the fragments claimed in part b) of claim 14 are directed towards fragments of full-length nucleotides SEQ ID NOs: 61, 63, or 65 comprising at least 62% of SEQ ID NOs: 61, 63, or 65, Gao anticipates the instantly claimed fragment, and therefore the rejection is maintained.
Regrading the rejection of claim 17 as obvious over Gao in further view of Kim et. al., Applicant argues that Gao and Kim do not teach or suggest every element of amended claim 14 (Remarks p. ). This is not persuasive as described above because Gao et. al. teaches the nucleic acid sequence fragment that is 62% identical to instant SEQ ID NO: 65, which reads on the best interpretation of the fragment that the Examiner could discern for expedited prosecution as described in the 112(b).
Applicant further argues that “Even given SEQ ID NO:19 from Gao, as a starting point, one of skill in the art could not have arrived at the present invention through routine optimization with a reasonable expectation of success. The degeneracy of the genetic code, while offering flexibility, introduces a vast number of possible nucleotide sequences that can encode the same amino acid sequence. Generation of an optimized sequence is not a routine matter but is necessarily an inventive process as it requires an inventor to provide input at multiple levels to achieve a desired result. One of skill in the art would have to attempt thousands of different codon permutations and validate the expression levels and immunomodulation properties of each of the resulting sequences. Because of this inherent unpredictability a skilled person would not have any expectation of success at arriving at the claimed invention in view of Gao and Kim. As such, Applicants submit that the synthetic sequences recited in claim 14 involve a high level of creative design input and are inventive”. This is not persuasive because, as described in the 112(b), 112(a), and 103 rejections above, the claims are not limited to the sequences Applicant is describing as inventive. For example, Applicant has designed and optimized codons for expression, translation efficiency, and codon usage of a single, particular anti-HER2 antibody comprising specific CDRs; the claims currently include nucleic acids encoding entirely distinct anti-HER2 CDRs, including some that have yet to be invented; additionally, the variability currently encompassed by the indefinitely claimed fragments and up to 95% identity in any portion of the nucleic acid allows for substitution of not only different degenerate codons that may or may not have the argued expression and translation efficiency, but may encode for entirely different antibodies than the instantly optimized antibody.
Double Patenting- Maintained, modifications necessitated by amendment
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.
Claim 14, 19, and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 40-45 of copending Application No. 18699081 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the '081 application anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 of the ‘081 application is directed at a nucleic acid molecule comprising a nucleotide sequence encoding a natural killer engager or fragment thereof comprising an antibody of fragment thereof that specifically binds to a sialic-binding receptor linked to an antibody or fragment thereof that binds to a target cell of interest. Claim 43 is directed towards the nucleic acid molecule wherein the tumor antigen is selected from FSHR, HER2, IL13Ra, EGFRvIII, and BARF1. Claim 44 recites wherein the nucleic acid encodes and amino acid selected from a group and recites SEQ ID NO: 8 which is 100% identical to instant SEQ ID NO: 66 and a nucleic acid of SEQ ID NO: 7 which is 81.1% identical to instant SEQ ID NO: 65 (including 640 matches; reads on identity to a fragment at least 65% of the length of SEQ ID NO: 65; see Result #4 Pending Applications .rnpm SEQ ID NO: 65 dated 12/3/2025). Claim 45 recites a composition comprising the nucleic acid and an excipient.
Claims 17 and 18 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 40-45 of copending Application No. 18699081 in view of Kim et. al. “Gene Therapy using plasmid DNA-encoded anti-HER2 antibody for cancers that overexpress HER2,” , published September 16, 2016 (Of record, PTO-892 dated 6/13/2025).
This is a provisional nonstatutory double patenting rejection.
The teachings of the ‘081 application in regards to instant claim 14 are in the NSDP rejection above. The claims of the ‘081 application do not explicitly teach the nucleic acid molecule of claim 14 wherein the nucleotide sequence is linked to a nucleic acid sequence encoding an IgE leader sequence (instant claim 17) or wherein the nucleic acid molecule comprises and expression vector (instant claim 18).
The teachings of Kim et. al. are in the 103 rejection above. To briefly summarize, Kim et. al. teaches an expression vector comprising an IgE leader sequence and encoding a conventional anti-HER2 antibody for gene therapy using a DNA vector to express an antibody in vivo.
It would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was filed to generate a nucleic acid molecule encoding one or more synthetic antibodies, wherein the nucleic acid molecule comprises a nucleotide sequence encoding the anti-HER2 antibody of the ‘081 claims and wherein the nucleotide sequence is operably linked to a nucleic acid sequence encoding an IgE leader sequence of Kim et. al. using the pVax1 expression vector appropriate for gene therapy as taught by Kim et. al. One of ordinary skill in the art would have been motivated to and would have had a reasonable expectation of success given Kim et. al. teaches and demonstrates successfully using an IgE leader sequence linked to their HER2 antibody for translation and production of their HER2 antibody in order to benefit from the anti-tumor efficacy and low production costs and simple manufacturing steps of gene therapy via in vivo antibody expression as taught by Kim et. al. Given the shared and established conventional HER2 antibodies taught by the prior art, one of skill in the art could have substituted the conventional HER2 antibody of ‘081 claims for the trastuzumab-based antibody in the construct of Kim et. al. and produced the plasmid encoding the HER2 antibody with a reasonable expectation of success.
Response to Arguments
The Remarks field 5/8/2026 have been fully considered. Applicant asked that the NSDP rejected be held in abeyance. A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Additionally, MPEP 804.I.B.1 states that provisional NSDP rejections should not be held in abeyance and that “an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner”. Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Allowable Subject Matter
The nucleotide sequence encoding one or more synthetic antibodies that bind HER2, wherein the nucleic acid molecule comprises a nucleotide sequence consisting of SEQ ID NO: 65 as recited in claim 14 part c) is free of the prior art.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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