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 .
Application Status
This action is written in response to applicant’s correspondence received 22 May 2026. Claims 1, 3-11, and 13-23 are currently pending. Claims 10 and 14-17 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 3-9, 11, 13, and 18-23 are examined herein. The restriction requirement mailed 6 August 2025 is still deemed proper. Applicant's elected Group I alongside the species of trastzumab with traverse in the reply filed 8 December 2025.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the
claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1, 3, 5-9, and 18-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hadlaczky (US Patent No. 8,389,802 B2) in view of Kim (Nucleic acids research 46.13 (2018): 6712-6725).
Regarding claim 1, the newly amended claim limitation reciting “ a genomic amplification drop site” is interpreted as being drawn towards nonfunctional descriptive material as described in MPEP 2111.05 because the phrase is descriptive terminology that doesn’t alter the structure of the amplification sites, which are defined by the claimed sequences.
Hadlaczky is drawn towards an invention concerned methods for preparing cell lines that contain artificial chromosomes and targeted insertion of heterologous DNA into the chromosomes (Col 2, lines 60-66). Hadlaczky teaches the use of homology targeting vectors (i.e., an expression vectors) that can incorporate heterologous genes (i.e., DNA fragments) into mammalian artificial chromosomes (i.e., into a region of open chromatin in mammalian cells) (Col 83, lines 44-60). Hadlaczky teaches that the homology targeting vectors may comprise a selectable marker (Col 83, lines 53-58), selected from puromycin (Col 83, lines 66-67). Hadlaczky teaches that the homology targeting vectors can both target a region of an artificial chromosome of interest and induce large scale amplification (i.e., the vectors include a targeting and amplification sequence) (Col. 82, lines 36-64). Hadlaczky teaches that the homology targeting vectors can encode a therapeutic gene of interest, including a cystic fibrosis transmembrane conductance regulator, that can be incorporated into the mammalian artificial chromosome (Col 83, lines 62-66). Hadlaczky teaches that preferred targeting sequences include mammalian ribosomal RNA (i.e., rRNA) gene sequences (i.e., rDNA) which target the heterologous DNA to integrate into the rDNA region of those chromosomes that contain rDNA (Col 5, lines 35-38).
Hadlaczky does not teach or suggest that the genomic amplification drop site targeting and amplification sequence comprises the claimed SEQ ID NO: 1 (Claim 1).
However, one of ordinary skill in the art would have considered the teachings of Kim as both references are common fields of endeavor pertaining to the study of rDNA.
Kim is drawn towards a study concerned with variations in human chromosome 21 rRNA genes characterized by TAR (i.e. transformation-assisted recombination) cloning (Abstract). Kim teaches the use of an rDNA sequence from a CDC27 pseudogene , termed “JH2”, that comprises an rDNA sequence having 100% identity to the claimed SEQ ID NO: 1 (pg. 6718; see attached sequence alignment). Kim teaches that a library of bacterial artificial chromosomes and yeast artificial chromosomes were able to be generated that contain the CDC27 pseudogene JH2 comprising the claimed SEQ ID NO: 1 (pg. 6718-6719; see Figure 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the rDNA targeting sequence of Hadlaczky for an rDNA sequence comprising a sequence having 100% identity to the claimed SEQ ID NO: 1, as described by Kim. A person of ordinary skill in the art would have been motivated to do so in order to utilize a known pseudogene sequence that can be utilized to generate an artificial chromosome via the targeting of an rDNA region of the chromosome through the use of an rDNA sequence. A person of ordinary skill in the art would have had a reasonable expectation of success because Hadlaczky teaches that targeting sequences may include rDNA sequences while Kim teaches that the claimed SEQ ID NO: 1 was present within a known rDNA sequence that could be integrated into an artificial chromosome.
Regarding the newly amended nonfunctional descriptive material comprising a “genomic amplification drop site”, because there is no structural difference between the claimed SEQ ID NO: 1 and the sequence having 100% identity to the claimed SEQ ID NO: 1 within the JH2 gene of Kim, the sequence of Kim is interpreted as encompassing the claimed a “genomic amplification drop site”.
Regarding claim 3, Hadlaczky teaches that the homology targeting vectors can encode a therapeutic gene of interest, including a cystic fibrosis transmembrane conductance regulator (i.e., a single protein) (Col 83, lines 62-66).
Regarding claim 7, Hadlaczky teaches that exemplary host cells include CHO cells (Col 35, lines 5-25).
Regarding claim 8, Hadlaczky teaches that thymidine kinase deficient murine L cells (i.e., mouse cells) may be used as a host for the artificial chromosome (Col 70, lines 36-49).
Regarding claim 9, Hadlaczky teaches that exemplary host cells include HEK 293 cells (i.e., human cells) (Col 35, lines 5-25).
Regarding claim 18, Hadlaczky teaches that exemplary host cells include CHO cells (i.e., mammalian cells) (Col 35, lines 5-25). Hadlaczky teaches that the homology targeting vectors can encode a therapeutic gene of interest, including a cystic fibrosis transmembrane conductance regulator, that can be incorporated into the mammalian artificial chromosome (i.e., the DNA fragment encoding a therapeutic protein can be integrated into the host cell’s open chromatin of the artificial chromosome) (Col 83, lines 62-66).
Regarding claims 5 and 21, Hadlaczky teaches that multiple copies of a heterologous gene can be integrated into the artificial chromosome in order to generate a megachromosome comprising 6 amplicons (i.e., 6 copies of a nucleic acid sequence encoding a protein of interest) (Col 13, lines 9-14, Col 52, lines 15-28; see Figure 3).
Regarding claim 6, Hadlaczky teaches that exemplary host cells include HEK 293 cells (i.e., human cells) (Col 35, lines 5-25).
Regarding claims 19-20, Hadlaczky teaches that the homology targeting vectors can encode a therapeutic gene of interest, including a cystic fibrosis transmembrane conductance regulator (i.e., a single protein), that can be incorporated into the mammalian artificial chromosome (Col 83, lines 62-66).
Claim(s) 4, 11, and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hadlaczky (US Patent No. 8,389,802 B2) in view of Kim (Nucleic acids research 46.13 (2018): 6712-6725) as applied to claims 1, 3, 5-9, and 18-20 above, and further in view of Blanco (Acta Pharmaceutica (2019)).
Regarding claims 4, 11, and 13, the teachings of Hadlaczky in view of Kim are discussed above as applied to claims 1, 3, 5-9, and 18-20.
Hadlaczky in view of Kim does not teach or suggest that the protein of interest is trastuzumab (Claims 4, 11, and 13).
However, one of ordinary skill in the art would have considered the teachings of Blanco as both references are common fields of endeavor pertaining to the use of nucleic acids encoding antibodies.
Blanco is drawn towards a study concerned with the binding properties and activity of a novel therapeutic monoclonal antibody (Abstract). Blanco teaches that trastuzumab is a monoclonal antibody that is directed against HER2: a growth factor receptor that is overexpressed in invasive breast adenocarcinomas (pg. 28). Blanco teaches the use of a DNA plasmid encoding trastuzumab that was able to be expressed in target cells of interest (pg. 28).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nucleic acid encoding an antibody of interest, as described by Hadlaczky in view of Kim, for a nucleic acid encoding trastuzumab, as described by Blanco. A person of ordinary skill in the art would have been motivated to do so in order to produce a therapeutic antibody that is directed against a receptor that is overexpressed in cancerous cells. A person of ordinary skill in the art would have had a reasonable expectation of success because both Blanco and Hadlaczky in view of Kim teach the use of nucleic acids encoding therapeutic antibodies.
Response to Arguments
Applicant's arguments filed 22 May 2026 have been fully considered but they are not persuasive.
Applicant alleges that the rDNA fragment of Hadlaczky originates from mouse in contrast to the claimed SEQ ID NOs: 1-5 which are human sequences corresponding to pseudogene CDC27, which are unrelated and distant from the intended target sequence of Hadlaczky (Remarks; pg. 12). Applicant alleges that contrary to what Hadlaczky teaches, the present invention does not try to target and to specifically integrate DNA fragments into rDNA regions or into alpha satellite regions (Remarks; pg. 14). Applicant alleges that while Hadlaczky targets the initial segment of the rDNA regions in the chromosomes, SEQ ID NO: 1 targets a very different position in the IGS region, specifically the CDC27 region, a pseudogene existing in multiple copies in the human genome (Remarks; pg. 14).
In response to applicant's argument that the purpose of Hadlaczky (i.e., the integration of DNA fragments into rDNA regions) differs from the claimed invention’s purpose (i.e., the integration of DNA fragments into human sequences corresponding to pseudogene CDC27), a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, the structure rendered obvious by Hadlaczky in view of Kim is capable of performing targeted integration of a DNA fragment into a region of interest in a chromosome present in a mammalian host cell through the use of a targeting sequence comprising the claimed SEQ ID NO: 1, as claimed. Thus, a person of ordinary skill in the art would expect that the structure of Hadlaczky in view of Kim would be able to perform the intended use alleged by Applicant wherein the structure could similarly target and integrate a DNA fragment in a human cell.
Additionally, modifying the vector of Hadlaczky such that it contained a targeting and amplification sequence comprising the claimed SEQ ID NO: 1 would not have rendered the vector inoperably because Hadlaczky teaches that preferred integration regions are rDNA regions, which Kim describes the claimed SEQ ID NO: 1 as being present within an rDNA sequence comprising a CDC27 pseudogene. Accordingly, one would have expected modifying the vector of Hadlaczky as proposed above to have resulted in a DNA vector that could integrate a heterologous DNA fragment at a CDC27 pseudogene.
Additionally, it is noted that claims 1 and 18 are limited to mammalian host cells, and not human host cells. Therefore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the targeting of GADS in human cells’ genomes) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, as discussed above, the newly amended claim limitation reciting “ a genomic amplification drop site” is interpreted as being drawn towards nonfunctional descriptive material as described in MPEP 2111.05 because the phrase is descriptive terminology that doesn’t alter the structure of the sites, which are defined by the claimed sequences. Thus, the artificial mammalian chromosome present in the mammalian cells described in Hadlaczky reads on the claimed “mammalian host cells” and the sequence having 100% identity to the claimed SEQ ID NO: 1 reads on the claimed “genomic amplification drop site” because there is no structural difference from a genomic amplification drop site and an amplification site present on an artificial chromosome present in a mammalian host cell.
Applicant alleges that an obviousness determination requires finding both that one of skill in the art would have been motivated to modify or combine the teachings of the prior art (Remarks; pg. 15). Applicant alleges that there is no description or suggestion in Kim for the use of CDC27 as a proven and efficient targeting sequence for chromosomal integration with the purpose of protein production in mammalian cell lines; therefore a person of ordinary skill in the art would not have been motivated to have selected the region the CDC27 pseudogene as a targeting and amplification sequence within the vector of Hadlaczky (Remarks; pg. 15). Applicant alleges that there is no suggestion in Hadlaczky in combination with Kim that would indicate which sequence from the 45 kb rDNA sequence in Kim could be used instead of the 4870 rDNA sequence of Hadlaczky (Remarks; pg. 15).
These arguments are not found persuasive because MPEP 2144 teaches that the references do not have to explicitly suggest to combine the teachings. Rather, establishing a prima facie case of obviousness requires a clear articulation of a rationale for combining the teachings of the references, and such rationale has been provided in the rejection above.
Applicant alleges that amplification has a special meaning in Hadlaczky which is different from the amplification of the inserted sequence, as understood in the present application (Remarks; pg. 14). Applicant alleges that in the present application, it has been experimentally proven that each of the GADS sequences of the present invention results in amplification of the inserted constructs (Remarks; pg. 16). Applicant alleges that based on the knowledge of a person skilled in the art, there was no reasonable expectation of success that the fragments of the present invention would be appropriate for amplification of the fragment plus the transgene (Remarks; pg. 16). Applicant alleges that it would not have been expected that an efficient and high-level expression of proteins would be achieved because there is no suggestion or indication in Hadlaczky that such sequences should be sought, and there is no suggestion or indication in Kim regarding the claimed use of the CDC27 pseudogene sequence or that any fragments thereof should have such a favorable effect (Remarks; pg. 16). Applicant alleges that the proposed modification would render the prior art inoperable or destroy its intended purpose (Remarks; pg. 16).
This argument is not found persuasive because Hadlaczky teaches that the amplification that produces the additional centromere or centromeres occurs in cells that contain chromosomes in which the heterologous DNA has integrated near the centromere in the pericentric region of the chromosome (i.e., the heterologous DNA is amplified such that additional copies of the heterologous DNA are present within the mammalian host cell) (Col. 5, lines 10-21). Hadlaczky also teaches that the heterologous DNA that is integrated into the artificial chromosome can be expressed such that a protein encoded by the heterologous DNA can be produced from the host cell (Col. 13, lines 26-36).
Accordingly, one of ordinary skill in the art would have expected that the vector of Hadlaczky could be successfully utilized to amplify the heterologous DNA segment and express said heterologous DNA segment from the generated artificial chromosome. Additionally, modifying the vector of Hadlaczky such that it contained the claimed SEQ ID NO: 1 would not have rendered the vector inoperably because Hadlaczky teaches that preferred integration regions are rDNA regions, which Kim describes the claimed SEQ ID NO: 1 as being present within an rDNA sequence comprising a CDC27 pseudogene. Accordingly, one would have expected modifying the vector of Hadlaczky as proposed above to have resulted in a DNA vector that could integrate a heterologous DNA fragment at a CDC27 pseudogene.
Applicant alleges that Claim 5 specifies that the mammalian host cell, once transformed with the expression vector, contains at least 5 copies of the nucleic acid sequence encoding the protein of interest and that no such information can be found in Hadlaczky and Kim (Remarks; pg. 16).
This argument is not found persuasive because Hadlaczky explicitly teaches that, and provides a working example of, a megachromosome comprising 6 amplicons, wherein each amplicon comprises a heterologous DNA fragment (i.e., 6 copies of a nucleic acid sequence encoding a protein of interest) that was integrated through the use of the vector (Col 13, lines 9-14, Col 52, lines 15-28; see Figure 3).
Response to Arguments
Applicant's arguments filed 22 May 2026 have been fully considered but they are not persuasive.
Applicant alleges that the disclosure of Blanco does not describe the CDC27 pseudogene as being useful in amplifying the DNA encoding trastuzumab (Remarks; pg. 17).
This argument is not found persuasive because the disclosure of Blanco was relied upon for the teaching of a heterologous DNA segment that encodes a beneficial therapeutic protein of interest, which could be substituted by a person of ordinary skill in the art for the DNA fragment encoding a therapeutic gene of interest as described by Hadlaczky.
Allowable Subject Matter
Claims 22-23 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claims 22-23, the closest prior art is Edwards (PG Pub No. EP 1541683 A1) and Edwards sequence alignment (accessed 21 August 2026). Edwards is drawn towards an invention concerned with mRNAs encoding human proteins (Abstract). Edwards teaches the use of a DNA sequence encoding a protein that comprises 99.5% sequence identity with the claimed SEQ ID NO: 5 (see SEQ ID NO: 11,435 in attached sequence alignment).
However, neither Edwards nor the prior art teaches or suggests the claimed SEQ ID NOs: 2-5, nor suggests that the claimed sequences were known regions of interest present within genomic amplification drop sites that could be targeted by the claimed expression vector present within a mammalian host cell (Claims 22-23)
Applicant has provided adequate written description for the claimed vector comprising the claimed SEQ ID NOs: 2-5 and teaches that SEQ ID NO: 2 (GADS2) corresponds to a 2993 bp segment next to GADS1 while SEQ ID NOs: 3 to 5 (GADS 3 to 5) are fragments of SEQ ID NO: 2 (GADS2) that could be utilized to integrate a DNA fragment encoding a protein of interest within a mammalian host cell (paragraphs [199] to [232] of the application).
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached Mon-Fri, 9AM-5PM (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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