DETAILED ACTION
Claims 1-21 are currently pending and under examination in the instant application. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/24/23 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this action.
Claim Objections
The claim listing filed on 8/22/23 is objected to for the following informalities: the claim numbering for each claim is presented in bold and in brackets, e.g. “[Claim 1]”, whereas the appropriate claim numbering simply uses the consecutive numbering of the Arabic numerals in a regular font. For example,
1.
2.
3.
etc.
Further, independent claims 1 and 17 use the abbreviation “RSS” without first providing a definition of this abbreviation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-21 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.
The claims are, in part, narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors. In particular, the claims as a whole are largely missing definite/indefinite articles such as “a” or “an” or “the” preceding each noun, and are further missing a number of conjunctions such as “and” or “wherein” or “whereby”. For example, claim 1 recites in the first two lines, “ A method for producing transgenic non-human animal cell having genome comprising humanized immunoglobulin gene locus..”. An indefinite or definite article is missing before the noun phrase “transgenic non-human animal cell”, before the noun “genome”, and before the noun phrase “humanized immunoglobulin gene locus”. The next three lines, lines 3-5, are further missing an indefinite or definite article before the nouns, “variable region” and “constant region”. Numerous further instances of missing indefinite/definite articles are present in the remainder of claim 1 and in claims 2-21. In addition, the lack of conjunctions such as “and”, “or”, “whereby”, or “wherein” prefacing the various limitations between commas, semi-colons, and colons renders the claims confusing as it is not clear whether these limitations are active steps, included or alternative elements, a recited result of a previous active step, or simply a description of a mechanism associated with the active step. For example, claim 1 recites in part, “ b) producing a plurality of microcells using the donor cell, at least one microcell among the plurality of microcells includes the donor chromosome; c) producing a fusion non-human animal cell by contacting at least one microcell with the recipient cell; the fusion non-human animal cell comprises the recipient chromosome and the donor chromosome;”. Without conjunctions, steps b) and c) are confusing as it is unclear whether the limitation after the comma or the semi-colon represent a separate element present in each active step or whether the limitation is describing the result of the active step. Note that claims 2-21 are likewise missing conjunctions between limitations present between semi-colons, colons, and commas and are thus also confusing and indefinite.
Further, the ending portion of step d) in claim 1 and claim 17, reproduced below, appears to read as two paragraphs in narrative form, particularly as the last few lines are indented and first word begins with a capital A:
“the recombinase recognizes the RRS for a first interchromosomal exchange and the RRS for a second interchromosomal exchange to induce recombination between the recipient chromosome and the donor chromosome; whereby variable region of the non-human animal immunoglobulin locus existing between the first and second RRS of the recipient chromosome is exchanged for the variable region of the human immunoglobulin locus between the third and fourth RRS of the donor chromosome;
As a result, a recombinant chromosome comprising variable region of a human immunoglobulin locus and constant region of an endogenous non-human animal immunoglobulin locus is generated”.
In addition to the lack of indefinite articles, definite articles, and conjunctions, and the narrative nature of portions of the claims, claims 1 and 17 are further indefinite in that it is unclear in the recitation, “the recombinase recognizes the RRS for a first interchromosomal exchange and the RRS for a second interchromosomal exchange” which RRS is recognized, as the previous portions of the claim refer to a first, second, third, and fourth RRS. While the claims do indicate previously, for example, that the first RRS and third RRS are for the first interchromosomal exchange, the later reference to “the RRS” is in the singular such that it is confusing as to which RRS the applicant means to reference in this limitation.
Claims 10 and 18-20 are further indefinite they recite the phrase “wherein in the a)” (claim 10), or “wherein in the e)” (claims 18-20). It is not clear what “the a)” or “the e)” are. It is presumed that applicant is attempting to reference “step a)” or “step e)”. If this is the case, it is suggested that applicant amend the claims to clarify that they are reference step a) or step e).
In the interests of compact prosecution, the claims have been interpreted based on their broadest reasonable interpretation.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims, 3, 5, 7, and 9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 3 depends on claim 2 which depends on claim 1. Claim 5 depends on claim 4 which depends on claim 1. Claim 7 depends on claim 6, which in turn depends on claim 1. Claim 9 depends on claim 8, which in turn depends on claim 1. Claim 1 recites in its final lines, “a recombinant chromosome comprising variable region of a human immunoglobulin locus and constant region of an endogenous non-human animal immunoglobulin locus is generated”. Claim 2 depends on claim 1 and recites, “wherein the non-human animal immunoglobulin locus is an non- human-animal immunoglobulin heavy locus, the human immunoglobulin locus is a human immunoglobulin heavy locus”. Thus, claim 2, read in the context of claim 1 limits the variable region of the human immunoglobulin locus in the recombinant chromosome to a variable region of a human immunoglobulin heavy locus and the constant region to a non-human immunoglobulin heavy constant region. Claim 3, which depends on claim 2, recites, “wherein the recombinant chromosome comprises a human immunoglobulin locus comprising variable region of a human immunoglobulin heavy locus and the constant region of an endogenous non-human animal immunoglobulin heavy locus”. However, as claim 2 has already limited the human immunoglobulin locus to a human immunoglobulin heavy locus and the non-human immunoglobulin locus to a non-human animal immunoglobulin heavy locus, claim 3 does not further limit claim 2.
Claim 4 depends on claim 1 and recites, “wherein the non-human animal immunoglobulin locus is an non- human-animal immunoglobulin kappa locus, the human immunoglobulin locus is a human immunoglobulin kappa locus”. Thus, claim 4, read in the context of claim 1 limits the variable region of the human immunoglobulin locus in the recombinant chromosome to a variable region of a human immunoglobulin kappa locus and the constant region to a non-human immunoglobulin kappa constant region. Claim 5, which depends on claim 4, recites, “wherein the recombinant chromosome comprises a human immunoglobulin locus comprising variable region of a human immunoglobulin kappa locus and the constant region of an endogenous non-human animal immunoglobulin kappa locus”. However, as claim 4 has already limited the human immunoglobulin locus to a human immunoglobulin kappa locus and the non-human immunoglobulin locus to a non-human animal immunoglobulin kappa locus, claim 5 does not further limit claim 4.
Claim 6 depends on claim 1 and recites, “wherein the non-human animal immunoglobulin locus is an non- human-animal immunoglobulin lambda locus, the human immunoglobulin locus is a human immunoglobulin lambda locus”. Thus, claim 6, read in the context of claim 1 limits the variable region of the human immunoglobulin locus in the recombinant chromosome to a variable region of a human immunoglobulin lambda locus and the constant region to a non-human immunoglobulin lambda constant region. Claim 7, which depends on claim 6, recites, “wherein the recombinant chromosome comprises a human immunoglobulin locus comprising variable region of a human immunoglobulin lambda locus and the constant region of an endogenous non-human animal immunoglobulin lambda locus”. However, as claim 6 has already limited the human immunoglobulin locus to a human immunoglobulin lambda locus and the non-human immunoglobulin locus to a non-human animal immunoglobulin lambda locus, claim 7 does not further limit claim 6.
Claim 8 depends on claim 1 and recites, “wherein the non-human animal immunoglobulin locus is an non- human-animal immunoglobulin kappa locus, the human immunoglobulin locus is a human immunoglobulin lambda locus”. Thus, claim 8, read in the context of claim 1 limits the variable region of the human immunoglobulin locus in the recombinant chromosome to a variable region of a human immunoglobulin lambda locus and the constant region to a non-human immunoglobulin kappa constant region. Claim 9, which depends on claim 8, recites, “wherein the recombinant chromosome comprises a human immunoglobulin locus comprising variable region of a human immunoglobulin lambda locus and the constant region of an endogenous non-human animal immunoglobulin kappa locus”. However, as claim 8 has already limited the human immunoglobulin locus to a human immunoglobulin lambda locus and the non-human immunoglobulin locus to a non-human animal immunoglobulin kappa locus, claim 9 does not further limit claim 8.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Takehara et al. (2014) Transgenic Res., Vol. 23, 441-453, in view of Wallace et al. (2007) Cell, Vol. 128, 197-209, Yang et al. (2017) Mol. Ther., Vol. 7, 378-386, WO 98/46733 (1998), hereafter referred to as Hernandez et al., and U.S. Patent Application Publication 2014/0017228 (2014), hereafter referred to as MacDonald et al.
Takehara et al. teaches a novel transchromosomic system for translocation of a human Mb-sized genomic fragment to a mouse chromosome (Takehara et al., page 441). As proof of concept, Takehara et al. exemplifies the translocation of human genomic sequence from Chr. 21 into mouse Chr.10 via the insertion of loxP sites into a target mouse Chr.10 in a mouse embryonic stem cell, insertion of loxP sites into human chromosome 21 present in a DT40 cell, followed by microcell mediated chromosome transfer (MMCT) of human chromosome fragments into mouse cells, and Cre/loxP-mediated chromosome translocation to generate the mouse chromosome 10 comprising a fragment of human chromosome 21 (Takehara et al., pages 441-442). Figure 1 and page 450 of Takehara diagrams the step by step process. In step 1, a lox P site encoding selectable markers is introduced into the terminal region of mouse Chr.10 between the centromere and the telomere using a targeting vector for homologous recombination comprising the loxP site and 5’ and 3’ mouse genomic sequence flanking the targeted insertion site. In step 2, a loxP site including different selectable markers was inserted into human Chr.21 between the centromere and the telomere using a second targeting vector comprising a loxP site. In step 3, the human telomere was replaced by an artificial telomere. In step 4, the modified human Chr.21 was transferred to CHO cells for the production of microcells, which were then transferred into the modified mouse embryonic stem cell comprising the modified mouse Chr.10 using MMCT. In step 5, chromosome translocation was mediated by Cre recombination resulting in two artificial chromosomes- a mouse Chr.10 comprising a fragment of human Chr. 21 and a human chromosome 21 comprising a fragment of mouse Chr. 10. Figure 1 also shows that the residual chromosome- the hChr.21/mChr.10ter chromosome-can be negatively selected using 6-TG. Figure 1 further includes the process of making a transgenic mouse using the mouse embryonic stem cell comprising the mChr.10/hChr.21 chromosome comprising injecting the ES cell into a mouse blastocyst and introducing the blastocyst into a mouse which can be bred and selected for germline transmission of the artificial chromosome (Takehara et al., Figure 1, page 443, and pages 446-447). While Takehara et al. exemplified the introduction of one loxP site in each of the mouse and human chromosomes such that recombination swapped the entire terminal region of mouse chromosome 10, including the telomere, with human chromosome 21 sequence including associated telomere, Takehara et al. further envisioned modification of this method for replacement of segments of the mouse genome with syntenic regions of the human genome similar to the RMGR (recombinase mediated genomic replacement) approach using human BAC, citing Wallace et al. (Takehara et al., page 449). Takehara et al. teaches that heterotypic lox sites can be introduced into human chromosomes in DT40 cells to enable larger scale replacements (Takehara et al., page 449).
While Takehara et al. suggest modification of their method to utilize heterotypic lox sites similar to the RMGR approach, Takehara et al. does not specifically describe the placements of multiple loxP sites for replacing segments of mouse chromosome with syntenic regions of a human chromosome. However, Takehara et al., as noted above, does point to the methods used by Wallace et al. as a guide. Wallace et al. supplements Takehara et al. by teaching a strategy for inserting heterotypic loxP sites for the specific replacement of any section of mouse chromosome with a syntenic section of human chromosome (Wallace et al., page 197). In Figure 4, Wallace shows the insertion of a first loxP site and second lox511 site flanking a mouse chromosomal region to be replaced, where both sites are situated between the telomere and centromere of mouse chromosome 11, and the insertion of a first loxP site and a second lox511 site flanking the human syntenic chromosomal region of a fragment of human chromosome 16 (Wallace et al., page 199, Figure 1, and page 202, Figure 4). Note as well that Wallace teaches the use of multiple specific targeting vectors for inserting the loxP and lox511 sites into the human and mouse chromosomes. Wallace further shows Cre/lox mediated translocation of the human chromosome 16 sequence between the heterotypic loxP sites replacing the mouse chromosome 11 sequence to generate an artificial mouse chromosome 11 comprising human chromosome 16 sequence (Wallace et al., Figure 4). It is also noted that Wallace et al. demonstrates that other site specific recombinases can be used to mediate recombination in a chromosome, such as frt and frt-f3 sites which can undergo recombination in the presence of the FLP recombinase (Wallace et al., Figure 4).
Therefore, in view of the specific teachings of Takehara et al. to modify their methods to allow for replacement of segments of a mouse chromosome with syntenic regions of a human chromosome using heterotypic loxP sites according to methods reported by Wallace et al., and the specific teachings of Wallace for strategies to place heterotypic recombination recognition sites (RRS) in each of the mouse and human chromosomes flanking the chromosomal sequence to be swapped using targeting vectors for each inserted RRS, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the strategy for generating an artificial mouse chromosome comprising a human chromosomal fragment taught by Takehara et al. to utilize the heterotypic RRS site placement taught by Wallace et al. in order to replace desired mouse chromosomal sequence with desired human chromosomal sequence via recombinase mediated chromosomal translocation with a reasonable expectation of success.
Takehara et al. further differs from the claimed methods as currently amended by not teaching to insert the loxP sites into human chromosomes which are in human cells. As noted above, Takehara et al. introduced the loxP sites in the human chromosome in chicken DT40 cells, and then transferred to the engineered human chromosome into hamster CHO cells prior to microcell fusion with mouse cells. Takehara et al. states that they used the DT40 cells because DT40 cells exhibit a high frequency of homologous recombination between DNA templates and chromosomes. Takehara et al. also states that they then transferred to the engineered human chromosome from DT40 cells to CHO cells because CHO cells exhibit higher efficiency microcell fusion.
However, while Takehara et al. decided to use both DT40 cells and CHO cells from the homologous recombination and microcell fusion steps, the prior art at the time of filing shows that alternative methods of introducing loxP cells into human chromosomes with high efficiency directly in human cells became available after the publication of Takehara et al.
Yang et al. teaches that they developed a CRISPR-Cas9 system for targeted introduction of loxP sites into a human chromosome in a human cell (Yang et al., page 378). Specifically, Yang et al. demonstrates the targeted introduction of loxP sequence into the human AAVS1 locus on human chromosome 19 in human embryonic kidney cells (HEK293) with high efficiency (Yang et al., pages 380-381). Thus, Yang et al. provides a novel method for introducing loxP sites directly into a human chromosome in a human cell with high efficiency without the need to remove the human chromosome and place it in a chicken DT40 cell, thus simplifying the step of engineering the human chromosome. Further, unlike DT40 cells which exhibit inefficient microcell fusion with mouse cells, microcells derived from human cells were known to be capable of efficient fusion with mouse cells. Hernandez et al. teaches performing homologous recombination in human HT cells to insert a marker cassette near the D21S55 locus in human chromosome 21, and then utilizing microcell mediated chromosome transfer protocol to successfully place the modified human chromosome 21 (HSA21) into a mouse embryonic stem cell (D3) (Hernandez et al., pages 4-5, and Figures 1-2 and 4). Thus, Hernandez et al. demonstrates that microcells derived from human cells can be used to efficiently and successfully to fuse with mouse cells including mouse ES cells.
Therefore, in view of the teachings of Yang et al. that CRISPR/Cas9 can be used for target site specific insertion of loxP sites into human chromosomes in human cells with high efficiency, and the teachings of Hernandez et al. that human microcells derived from human cells with a modified human chromosome can be efficiently and successfully fused to mouse cells, it would have been prima facie obvious to the skilled artisan at the time of filing to modify the methods of Takehara et al. in view of Wallace et al., which utilized both chicken DT40 cells and hamster CHO cells as intermediaries in the processes of making an engineered human chromosome and performing microcell fusion to introduce the engineered chromosome into mouse cells respectively, by instead introducing the loxP sites directly into the target human chromosome sites in human cells, and then to make microcells directly from the modified human cells and use those human microcells to fuse with mouse cells such as mouse ES cells as the exclusion of the intermediate steps using the chicken and hamster cells would substantially simplify the methods of Takehara et al. in view of Wallace et al. with predictable results.
While Takehara et al., Wallace et al., Yang et al., and Hernandez et al. provide the teachings and motivation to replace a portion of a mouse chromosome with a human chromosome using the method steps as claimed as discussed in detail above, none of the references specifically teach that the portion of the mouse and human chromosomes which are to be exchanged comprise an immunoglobulin locus, or more specifically a heavy or light chain immunoglobulin locus comprising variable region gene segments. Further, while Takehara et al. does teach the generation of mouse ES cells comprising the chimeric mouse/human chromosome, the injection of the mouse ES cells into a mouse embryonic blastocyst, and implantation into a surrogate in order to produce a transgenic mouse, Takehara et al. does not teach alternative methods involving the use of SCNT or the direct modification of a mouse embryo.
In regards to the human and mouse loci to be exchanged, Takehara et al. and Wallace et al. do provide general guidance for interchromosomal exchange of genomic sequence/loci, but do not suggest to exchange the variable region of for example the immunoglobulin kappa light chain locus, or the immunoglobulin lambda light chain locus, or the immunoglobulin heavy chain locus, in order to generate a recombinant mouse chromosome in which a variable portion of one of these loci has been replaced with corresponding human chromosomal variable region sequence, while retaining the constant region portion of the mouse loci. However, at the time of filing, the prior art provided substantial teachings and motivation to generate knockin chromosomes in the mouse in which the mouse endogenous unrearranged heavy chain, and/or light chain genomic loci were modified by replacing the endogenous mouse unrearranged V, (D), and J gene segments with human unrearranged V, (D), and J gene segments such that inserted human variable region gene segments were operably linked to the endogenous mouse constant region gene segments and further capable of rearranging to express a functional chimeric human/mouse heavy and/or light chains comprising human variable regions and mouse constant regions. MacDonald et al., for example, teaches to generate transgenic mice whose genome present in a chromosome has been modified by replacing all or substantially all of the endogenous VH, DH, and JH heavy chain gene segments with all or substantially all of the human VH, DH, and JH heavy chain gene segments 5’ of the endogenous mouse heavy chain constant region gene segments (MacDonald et al., paragraphs 51-55, 67, and Figure 1A). MacDonald et al. further teaches to generate transgenic mice whose genome present in a chromosome has been modified by replacing all or substantially all of the endogenous VL and JL light chain gene segments with all or substantially all of the human VL and JL light chain gene segments 5’ of the endogenous mouse light chain constant region gene segments, where the endogenous mouse light chain locus is either the kappa light chain locus or the lambda light chain locus and the human light chain VL and JL gene segments are either the human kappa light chain gene segments or lambda light chain gene segments (MacDonald et al., paragraphs 71, 120, 183, and 187-188, and Figure 1B). In particular, MacDonald et al. teaches that the human kappa light chain variable region genomic sequence is inserted 5’ of the endogenous mouse kappa light chain constant region sequences (see MacDonald et al. Figure 1B), or where the human lambda light chain variable region genomic sequence is inserted 5’ of either the endogenous mouse lambda light chain loci constant region sequences or the endogenous mouse kappa light chain loci constant region sequences (see MacDonald et al., paragraph 183, and 187-188). MacDonald et al. teaches that the mice expressing the chimeric antibodies are useful for developing therapeutic antibodies for humans (MacDonald et al., paragraphs 4-6). MacDonald et al. also teaches alternatives to using modified ES cells to generate transgenic mice including the generation of mice using cells obtained from the nuclear transfer of nuclei from a diploid cell comprising the modified genome (MacDonald et al., paragraph 140-141, 176). Note that a diploid mouse cell is a somatic cell. MacDonald et al. teaches that the modified cell can also be an embryo (MacDonald et al., paragraphs 147, and 286).
Therefore, in view of the motivation to replace endogenous mouse immunoglobulin loci variable regions with human immunoglobulin loci variable regions, including the replacement of a mouse heavy chain loci variable region with a human heavy chain loci variable region, the replacement of a mouse kappa light chain loci variable region with a human kappa light chain loci variable region, the replacement of a mouse lambda light chain loci variable region with a human lambda light chain loci variable region, and the replacement of a mouse kappa light chain loci variable region with a human lambda light chain loci variable region as taught by MacDonald et al., and the further teachings of MacDonald et al. for methods of producing a transgenic using either a genetically modified cell obtained from somatic cell nuclear transfer or a genetically modified embryo, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize the methods of interchromosomal exchange taught by Takehara et al., in view of Wallace et al., Yang et al., and Hernandez et al. in order to generate a mouse ES cell, embryo, or progenitor cell derived from SCNT whose genome includes a mouse chromosome comprising a replacement of the endogenous immunoglobulin heavy or light chain variable region chromosomal sequence with human chromosomal sequence comprising the human immunoglobulin heavy chain or light chain variable region with a reasonable expectation of success, and to further use the ES cell, embryo, or progenitor cell obtained through SCNT to produce a transgenic mouse also 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.
Claims 1-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 17/565,302, hereafter referred to as the ‘302 patent, in view of U.S. Patent Application Publication 2014/0017228 (2014), hereafter referred to as MacDonald et al.
The ‘302 patent claims are both broader and narrower than the instant claims. The ‘302 patent claims recite a more detailed method of modifying mouse and human chromosomes in mouse and human cells respectively using multiple RSS flanking sequence to be exchanged using the same steps as claimed. While the steps recited in the ‘302 patent claims are more detailed that those in the instant claims, they are at the same time broader in that the ‘302 patent claims do not limit the sequence to be exchanged to immunoglobulin loci sequence. However, at the time of filing, the prior art provided substantial teachings and motivation to generate knockin chromosomes in the mouse in which the mouse endogenous unrearranged heavy chain, and/or light chain genomic loci were modified by replacing the endogenous mouse unrearranged V, (D), and J gene segments with human unrearranged V, (D), and J gene segments such that inserted human variable region gene segments were operably linked to the endogenous mouse constant region gene segments and further capable of rearranging to express a functional chimeric human/mouse heavy and/or light chains comprising human variable regions and mouse constant regions. MacDonald et al., for example, teaches to generate transgenic mice whose genome present in a chromosome has been modified by replacing all or substantially all of the endogenous VH, DH, and JH heavy chain gene segments with all or substantially all of the human VH, DH, and JH heavy chain gene segments 5’ of the endogenous mouse heavy chain constant region gene segments (MacDonald et al., paragraphs 51-55, 67, and Figure 1A). MacDonald et al. further teaches to generate transgenic mice whose genome present in a chromosome has been modified by replacing all or substantially all of the endogenous VL and JL light chain gene segments with all or substantially all of the human VL and JL light chain gene segments 5’ of the endogenous mouse light chain constant region gene segments, where the endogenous mouse light chain locus is either the kappa light chain locus or the lambda light chain locus and the human light chain VL and JL gene segments are either the human kappa light chain gene segments or lambda light chain gene segments (MacDonald et al., paragraphs 71, 120, 183, and 187-188, and Figure 1B). In particular, MacDonald et al. teaches that the human kappa light chain variable region genomic sequence is inserted 5’ of the endogenous mouse kappa light chain constant region sequences (see MacDonald et al. Figure 1B), or where the human lambda light chain variable region genomic sequence is inserted 5’ of either the endogenous mouse lambda light chain loci constant region sequences or the endogenous mouse kappa light chain loci constant region sequences (see MacDonald et al., paragraph 183, and 187-188). MacDonald et al. teaches that the mice expressing the chimeric antibodies are useful for developing therapeutic antibodies for humans (MacDonald et al., paragraphs 4-6). MacDonald et al. also teaches alternatives to using modified ES cells to generate transgenic mice including the generation of mice using cells obtained from the nuclear transfer of nuclei from a diploid cell comprising the modified genome (MacDonald et al., paragraph 140-141, 176). Note that a diploid mouse cell is a somatic cell. MacDonald et al. teaches that the modified cell can also be an embryo (MacDonald et al., paragraphs 147, and 286).
Therefore, in view of the motivation to replace endogenous mouse immunoglobulin loci variable regions with human immunoglobulin loci variable regions, including the replacement of a mouse heavy chain loci variable region with a human heavy chain loci variable region, the replacement of a mouse kappa light chain loci variable region with a human kappa light chain loci variable region, the replacement of a mouse lambda light chain loci variable region with a human lambda light chain loci variable region, and the replacement of a mouse kappa light chain loci variable region with a human lambda light chain loci variable region as taught by MacDonald et al., and the further teachings of MacDonald et al. for methods of producing a transgenic using either a genetically modified cell obtained from somatic cell nuclear transfer or a genetically modified embryo, it would have been obvious to the skilled artisan at the time of filing to utilize the methods of ‘302 patent in order to generate a mouse ES cell, embryo, or progenitor cell derived from SCNT whose genome includes a mouse chromosome comprising a replacement of the endogenous immunoglobulin heavy or light chain variable region chromosomal sequence with human chromosomal sequence comprising the human immunoglobulin heavy chain or light chain variable region with a reasonable expectation of success, and to further use the ES cell, embryo, or progenitor cell obtained through SCNT to produce a transgenic mouse also with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634