DETAILED ACTION
The present application is being examined under the pre-AIA first to invent provisions.
Applicants’ amendments and arguments filed on July 7, 2026, have been received and entered. Claims 2-3, 26, 32-33, 35, 39 have been amended, while claims 1, 4, 5-11, 25, 27-31, 36, 38 have been canceled. Claim 40 is newly added. Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 are pending in the instant application.
Election/Restrictions
Applicants’ election of claims 1-13, 17-25 (group I) in the reply filed on October 27, 2020, was acknowledged. It is noted that restriction requirement between invention of group I and II was withdrawn in office action mailed on 11/18/2020.
Priority
This application is a continuation of application no 13/310,431 filed on 12/02/2011, which is a CIP of PCT/GB2011/050019 filed on 01/07/2011 and CIP of PCT/GB2010/051122 filed on 07/07/2010 that claims priority from US provisional application no 61/355,666 filed on 06/17/2010 and US provisional application no 61/223,960 filed on 07/08/2009, which claims priority from foreign application UK 0911846 4 and UK 0913102 filed on .07/08/2009.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/14/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 are under consideration.
Allowable Subject Matter
The following claim is drafted by the examiner and considered to distinguish patentably over the art of record in this application, claim is presented to applicant for consideration:
An isolated cell comprising a chimeric immunoglobulin kappa locus comprising a human kappa variable (V) region at a mouse kappa locus comprising an endogenous mouse kappa C gene segment, wherein said human kappa V region comprises unrearranged human immunoglobulin kappa V and J gene segments,
wherein said chimeric immunoglobulin kappa locus comprises in 5' to 3' transcriptional order said unrearranged human kappa variable region gene segments, truncated human Igk JC intronic DNA, truncated mouse Igk JC intronic DNA comprising a kappa enhancer comprising 782 bp of mouse intron DNA, and said mouse kappa C gene segment;
wherein all or part of mouse Igk variable region DNA is present upstream of said unrearranged human immunoglobulin kappa V and J gene segments, wherein expression of Ig kappa chains comprising a mouse variable region is reduced or prevented; and wherein said cell is capable of expressing a chimeric kappa light chain encoded by said human kappa VJ gene joined to a mouse kappa C gene segment, and
wherein said cell is capable of expressing a chimeric kappa light chain encoded by said human kappa VJ gene joined to a mouse kappa C gene segment, wherein said isolated cell is selected from the group consisting of a mouse embryonic stem cell (ES), a mouse induced pluripotent stem cell (iPS), a mouse B cell and a mouse hybridoma cell thereof, wherein each of said mouse B cell and said mouse hybridoma B cell is capable of undergoing rearrangement of said human unrearranged human kappa V and J gene segments to form and express said human kappa VJ gene operatively joined to a mouse kappa C gene segment, and wherein each of said mouse ES cell and said mouse iPS cell is capable of undergoing rearrangement of said human unrearranged human kappa V and J gene segments to form and express said human kappa VJ gene operatively joined to a mouse kappa C gene segment following differentiation into a progeny B-cell..
Maintained & New-Claim Rejections - 35 USC § 112-in modified form
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 2, 6, 12-24 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an isolated mouse cell comprising a chimeric immunoglobulin kappa locus comprising a human kappa variable (V) region at a mouse kappa locus comprising an endogenous mouse kappa C gene segment, wherein said human kappa V region comprises unrearranged human immunoglobulin kappa V and J gene segments, wherein said chimeric immunoglobulin kappa locus comprises in 5' to 3' transcriptional order said unrearranged human kappa variable region gene segments, truncated human Igk JC intronic DNA, truncated mouse Igk JC intronic DNA comprising a kappa enhancer comprising 782 bp of mouse intron DNA, and said mouse kappa C gene segment;
wherein all or part of mouse Igk variable region DNA is present upstream of said unrearranged human immunoglobulin kappa V and J gene segments, wherein expression of Ig kappa chains comprising a mouse variable region is reduced or prevented; and wherein said cell is capable of expressing a chimeric kappa light chain encoded by said human kappa VJ gene joined to a mouse kappa C gene segment,
wherein said isolated cell is selected from group consisting of a mouse embryonic stem cell (ES), a mouse induced pluripotent stem cell (iPS), a mouse B cell and a mouse hybridoma cell thereof, wherein each of said mouse B cell and said mouse hybridoma B cell is capable of undergoing rearrangement of said human unrearranged human kappa V and J gene segments to form and express said human kappa VJ gene operatively joined to a mouse kappa C gene segment, and wherein each of said mouse ES cell and said mouse iPS cell is capable of undergoing rearrangement of said human unrearranged human kappa V and J gene segments to form and express said human kappa VJ gene operatively joined to a mouse kappa C gene segment following differentiation into a progeny B-cell,
does not reasonably provide enablement for any other cell or somatic cell derived from any other species comprising the chimeric immunoglobulin kappa (k) locus or a cell without any resulting phenotype as broadly claimed.
Applicants disagree with the rejection arguing that claim 2 "does not reasonably provide enablement for any other cell comprising a chimeric immunoglobulin kappa (k) locus", Applicant point to para. 481-499 of the instant specification for the enabled support for the claimed isolated cells. Applicant argues that the non-human cell can comprise not only eukaryotic cells such as CHO cells, but also bacterial cells such as DH10B cells which Adams teaches are used to carry the BAC clones⁴. This is applicable if using the methods disclosed in Applicant's published application, BAC clones could also contain a BAC library which is based on cells of the instantly disclosed engineered mice containing an unrearranged chimeric kappa light chain locus. Applicant notes that expression is not required by all cells of the instant claims. For instance, baculovirus-derived DNA in stably transduced CHO cells can be used also for gene manipulation. Applicant notes that the specification discloses how to make and use the claimed cell (see para. 27), Applicant notes that the genes encoding the heavy and light chains of non- mouse mammalian species e.g., swine, rabbits and sheep antibodies are organized in basically a similar manner as mouse and human. Applicants’ arguments have been fully considered but are not found persuasive.
As an initial matter, in view of applicants’ arguments and amendments to claim 3 and claims dependent therefrom, which now requires expression of the recited chimeric Igk locus accordingly restricts the cell to a mouse B cell, a mouse B cell hybridoma, a mouse ES cell and a mouse iPS cell, obviates the basis of the rejection. Therefore, the previous rejections of claim 3 and claims dependent therefrom are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
To the extent applicant’s argument pertains to the standing rejection of claim 2 and claims dependent therefrom, they are addressed as follows:
It is relevant to note that the scope of previously rejected claims have been broadened to include the isolated cell being selected from group consisting of isolated cell is selected from group consisting of a mouse embryonic stem cell (ES), a mouse induced pluripotent stem cell (iPS), a mouse B cell and a mouse hybridoma cell thereof . Therefore, applicants’ argument that instant specification enables a hybridoma cell or a B cell or an IPSC comprising a chimeric immunoglobulin kappa locus is moot.
Applicants point to various sections of instant specification to assert that instant specification discloses how to make and use the claimed cells. (see para. 143-145 and 174) Applicants’ arguments have been fully considered but are not found persuasive.
In response it is noted that breadth of claims encompass in 5' to 3' transcriptional order said unrearranged human kappa variable region gene segments, truncated human IgK JC intronic DNA, truncated mouse IgK JC intronic DNA comprising a kappa enhance at a mouse kappa locus (emphasis added), wherein all or part of mouse Igk variable region DNA is present upstream of said unrearranged human immunoglobulin kappa V and J gene segments, It is noted that para 374 [379] of the specification discloses an isolated host cell (eg, a hybridoma or a CHO cell or a HEK293 cell) comprising a nucleotide sequence according to aspect 129 or 130, wherein the nucleotide sequence encoding a heavy chain variable region of an antibody or fragment of aspect 126 (see para. 377 of the published application). The cited paragraph clearly shows that CHO cell or HEK cell comprises rearranged Ig gene segment, while claimed isolated cell require unrearranged human kappa variable region gene segments. It is emphasized that the nucleotide sequence encoding a heavy/kappa chain variable region of an antibody is not the same as the nucleotide sequence of an unrearranged variable gene segment because the heavy /kappa chain variable region is generated by somatic recombination of multiple gene segments (VDJ/VJ), whereas the unrearranged segment is a single, germline sequence. Likewise, the specification fails to disclose an isolated CHO, HEK 293 or any other somatic cell of any species comprising unrearranged human kappa variable region gene segments at a mouse kappa locus. It is known in prior art that mouse kappa locus relies on specific promoters and enhancers (such as the intronic and 3' κ enhancers) to drive high-level expression during B-cell maturation. In the instant case, Figures 14 - 18 of the instant specification describe a chimeric lg Kappa locus disclosed therein, in which human kappa variable region gene segments are positioned at the mouse endogenous lg Kappa locus (emphasis added). The guidance provided in the specification is limited to insertion of the landing pad for location of the human VK-JK gene segments into an endogenous lg Kappa locus is positioned between the last endogenous mouse Jk5 gene segment and the endogenous mouse Kappa Ei enhancer at a specific coordinate 70,674,735. These co-ordinates refer to NCBIM37 for the mouse genome
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The specification fails to teach if transcription factors can interact with some other mammalian promoters, as mouse regulatory elements do not function within a porcine nuclear environment. Additionally, the specification is silent on a 782bp of mouse intron exist between the iEK enhancer and 3 end of the recited human Ig kappa JC intron positioned at different species of cells derived from mouse or any other mammalian species. It is emphasized that claims neither recite a resulting phenotype nor last endogenous mouse Jk gene segment, VK-JK gene segments into an endogenous lg Kappa locus, one of skill in the art would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. Further art teaches rabbit, chicken, pig, sheep, and cow, diversity of the primary repertoire is generated through templated gene conversion between different variable region genes and non-templated hypermutation (Butler, supra, pages 43-70). Since the mechanism for producing heavy and light chain genes from germline sequence is different in animals such as pigs, sheep, cows, and chickens, from that used in mice and humans, the skilled artisan would not have been able to predict without undue experimentation whether a human immunoglobulin V, (D), and J/VJ genes segments is capable of undergoing successful rearrangement in different cells (somatic or ES cells or B cell) isolated from different animal species as required by claim to make and use the invention. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
In response to applicants’ argument that instant specification discloses host cell that includes a CHO cell or a HEK293 cell, it is noted that specification it is known that somatic cells do not generally express Rag1 and Rag2 that is required to be expressed along with TdT to make and use the cell. As stated in previous office action, not all somatic cells or isolated eukaryotic cells efficiently induce V(D)J recombinase activity to make enabled use of such cells. This is evident from the teaching of Oettinger et al (Science, 1990, 1517-1523) who reported RAG-1 inefficiently induced V(D)J recombinase activity when transfected into fibroblasts, but co transfection with an adjacent gene, RAG-2, has resulted in at least a 1000-fold increase in the frequency of recombination. The teaching of Oettinger supports the fact that non-lymphoid cells normally could not perform recombination (see abstract). In the instant case, neither specification nor prior art teaches V-DJ/VJ recombination of immunoglobulin in a non-lymphoid cell. The specification is silent on functioning of an unrearranged kappa locus that is entirely cell-type independent. The art teaches VDJ recombination is limited to lymphoid cells. It is further noted that claims 3 and 5 require the unrearranged human kappa V and J gene segments are capable of undergoing rearrangement sufficient to form a human kappa VJ gene operatively joined to a mouse kappa C gene segment to make and use the invention. Thus, claims dependent therefrom are not enabling for genus of isolated cell embraced by the breadth of the claims. One of ordinary skill in the art would have to perform undue experimentation to the express the chimeric immunoglobulin kappa (K) locus in the cell broadly claimed to make and use the invention, without reasonable expectation of success.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 1, 26, 29 and 31 are rejected remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (US Patent no 6596541, dated 07/22/2003) as evidenced by Murphy (2, US 8,791,323), Stevens et al (Pharma Focus Asia, 2008, 8, 72-74), Aguilera et al (EMBO 4(13B): 3689-3693, 1985) and Tanamachi et al (W02007/117410)/Morrison et al (US 5,807,715, dated 9/15/1998)/Wagner (Eur. J. Immunol. 1994, 24: 2672-2681) as applied above and further in view of Mendez et al (Nature genetics, 1997, 15(2), 146-156, IDS). Applicants’ cancellation of claims 1, 29 and 31 renders their rejections moot.
Maintained -Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 2, 6, 13-18, 20, 22-23 remain rejected are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (US Patent no 6596541, dated 07/22/2003) as evidenced by Murphy (2, US 8,791,323) and Stevens et al (Pharma Focus Asia, 2008, 8, 72-74), Aguilera et al (EMBO 4(13B): 3689-3693, 1985) and Tanamachi (W02007/117410)/Morrison et al (US 5,807,715, dated 9/15/1998) /Wagner (Eur. J. Immunol. 1994, 24: 2672-2681).
Applicants’ cancellation of claims 1, 7-9, 11, 29, 31, 36 and 38 renders their rejections moot. In view of applicant’s amendments to claim 3 limiting the scope of isolated cells that is capable of undergoing rearrangement obviates the basis of rejection of claims 3, 5, 26, 32, 33-35, 37, 39 and 40. Therefore, previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claim interpretation: Recitation of kappa variable region comprises 110 kb of human kappa variable region or comprises 250 kb kb of human kappa variable region DNA comprising unrearranged human immunoglobulin kappa V and J gene segment do not preclude a longer human kappa variable region comprising 110kb or 250 kb of human kappa variable region DNA (see claim 1). It is relevant to point out the transitional phrase “comprising” is interpreted as synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). Claims 2-3, 6-9, 13-18, 20, 22-23, 26, 32-33, 35 and 36 do not recite any specific phenotype such as cells capable of expressing chimeric kappa light chain or isolated cells capable of rearranging human VJ gene segment and capable of producing antibody.
Claim 2 are directed to an isolated cell comprising an unrearranged human immunoglobulin kappa V and J gene segments.
With respect to claims 2, 6, 14-18, Murphy teaches an isolated mouse embryonic cell comprising a genetically modified unrearranged immunoglobulin variable region gene locus, wherein the mouse heavy chain variable region locus is replaced with a human heavy chain variable gene locus and wherein the mouse kappa light chain variable region locus is replaced with a human kappa light chain variable region locus (see claims 13-15 of ‘541). It is further disclosed that the L TVEC is capable of accommodating large DNA fragments greater than 20 kb, and in particular large DNA fragments greater than100 kb" (col. 4, 10-14). It is relevant to note that said genetically modified cells is capable of producing a hybridoma expressing the hybrid antibody from the genetically modified mouse of the invention that is stimulated with the antigen Murphy discloses genetically modified cells as discussed supra is capable of producing-mouse from performing the equivalent variable region substitutions on the lambda and kappa light chain loci and heavy chain loci and breeding all three hybrid loci to homozygocity together in the same mouse (limitation of claims 17-18). The resultant transgenic mouse will have a genome comprising entirely human heavy and kappa light chain variable gene loci operably linked to entirely endogenous mouse constant region such that the mouse produces a serum containing an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. Such a mouse may then be used as a source of DNA encoding the variable regions of human antibodies and using standard recombinant technology, DNA encoding the variable regions of the heavy and light chains of the antibody is operably linked to DNA encoding the human heavy and light chain constant regions in cells, such as a CHO cells, which are capable of expressing active antibodies (see col. 27 and 28). In a preferred is a method of wherein the DNA of described above is isolated from a hybridoma created from the spleen of the mouse exposed to antigenic stimulation in described above (see col. 9, col. 1 lines 13-15). The resultant hybrid immunoglobulin loci will undergo the natural process of rearrangements during B-cell development to produce the hybrid antibodies" (col. 24, col. 2, lines 5-10) (limitation of claims 5, 9). In view of foregoing, Murphy discloses a B cell, a hybridoma, and a host cell comprising a human kappa variable (V) region at an endogenous kappa locus, wherein said human kappa V region comprises the entire (i.e., greater than 100 kb) of the human kappa variable region DNA comprising unrearranged human immunoglobulin kappa V and J gene segments.
Murphy et al teach there is a direct substitution of the human V-D-J/V-J regions for the equivalent regions of the mouse loci all of the sequences necessary for proper transcription, recombination, and/or class switching will remain intact. For example, the murine immunoglobulin heavy chain intronic enhancer, Em, has been shown to be critical for V-D-J recombination as well as heavy chain gene expression during the early stages of B cell development (col. 24, lines 32-40). Murphy discloses mouse that is able to produce hybrid antibodies having human variable regions and mouse constant regions. Since Murphy teaches direct substitution of human V-D-J/V-J regions for the equivalent regions of the mouse loci such that variable gene segment of heavy and light chain is operably linked to endogenous (mouse) constant region and therefore such as cell does not comprise a human immunoglobulin heavy chain and/or kappa chain constant region (see col. 24 and col. 27) (limitation of claims 3-5, 14-16 and 25).
With respect to claims 14-17, Murphy contemplated replacement in whole or in part of mouse Ig variable loci with human variable gene loci, such a replacement results in human V(D)J regions being inserted in overlap with the last 3' non-human mammal J region. Further the mouse disclosed by Murphy teach a mouse comprising a human VDJ DNA inserted into the mouse immunoglobulin locus in part within the genomic interval defined by the last 3' J region and the host constant region (see figure 4B). It is further disclosed that construct comprises gene segment V6-1 to JH6 in human germline order that is operably linked to endogenous mouse constant region (see figure 4a). Further since Murphy teaches contemplated replacement in whole or in part of mouse Ig variable loci with human variable gene loci therefore any remaining part of mouse IgK/IgH variable region DNA is present upstream of said unrearranged human immunoglobulin kappa V J/VDJ gene 85Attorney Docket No. 39080-17501 Electronically filed June 18, 2020 segments that expression of Ig kappa/heavy chains comprising a mouse variable region would implicitly be prevented or reduced.
Likewise, Stevens teaches a genetically modified mouse ES cells prepared by removing the ~3 megabase murine variable genomic sequences at the heavy and kappa light chain Ig loci in mouse ES cells, followed by the stepwise insertion of the umearranged human heavy and kappa light chain variable genomic loci, or~ 1 megabase of genomic DNA of the human heavy chain locus and 0.5 megabase of the human kappa light chain locus (see page 74), Figure 2) (limitation of claim 1-3, 5-9, 14-16). Stevens essentially disclose that the entire hu an Ig heavy and kappa light chain variable repertoire has been integrated into ES cells. The resulting genomic loci are stable throughout multiple generations of mice and have been shown to be used productively, generating antibodies of diverse variable sequences (see page 74). It is disclosed that the antibodies produced by the mouse possess mouse constant regions, and lacks human kappa and/or human heavy chain constant region. (see page 74).
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Stevens teaches the chimeric immunoglobulin kappa locus comprising in 5' to 3' transcriptional order said unrearranged human kappa variable region gene segments, truncated human Igk JC intronic DNA, a human/mouse junction, a human Igk JC intronic DNA and a mouse Igk JC intronic DNA comprising a kappa enhancer, and said mouse kappa constant region comprising said endogenous mouse kappa C gene segment (see figure 2). The ES cells comprising a human heavy chain variable region operably linked to a mouse heavy chain constant region and human kappa variable gene operably linked to endogenous kappa chain constant region as disclosed by Murphy/Stevens is structurally and functionally similar to one claimed in the instant application. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
Murphy/Stevens differ from claimed invention by not explicitly disclosing (i) chimeric immunoglobulin kappa locus comprises truncated mouse Igk JC intronic DNA comprising a kappa enhancer, and (ii) wherein said homozygous heavy chain Ig locus comprises in 5' to 3' transcriptional orientation: said unrearranged human heavy chain variable region gene segments comprising human IgH V gene segments, human D gene segments and human IgH J gene segments, truncated human IgH JC intronic DNA, a truncated mouse IgH JC intronic DNA, said enhancer and said mouse heavy chain constant region comprising said endogenous mouse constant gene segment and wherein the distance from said 3' human JH gene segment to said truncated mouse JC intron DNA is less than 2 kb.
Aguilera teaches that Ig heavy chain enhancer in the intron separating the JH region and the Cμ exons in mice (p. 3689, col. I). It is further disclosed that that the identified enhancer is typically about 1 kb or less from the 3' J gene segment (see 1 kb scale bar, figure 1A). The combination of reference differs from claimed invention by not explicitly disclosing chimeric JC intron comprising human JC intron contagious with truncated mouse JC intronic intron.
Tanamachi discloses the concept of mouse/human chimeric DNA. It is noted that the human/mouse chimeric DNA of Tanamachi et al. contains a ~400 bp human DNA downstream and contiguous with the 3' end of human JH6 and the mouse J/C intron, generating a J/C intron (see figure 1).
Tanamachi further teaches isolating B-cell (see page 19, line 32) or hybridoma (see page 20, line 1) from a mouse prepared from genetically modified ES cells. Tanamachi disclose that the mouse of the invention comprises, in 5' to 3' direction, a plurality of human Vh regions, a plurality of human D segments, a plurality of human JH segments, a mouse J-mu enhancer, a mouse p switch region and a mouse p constant region, wherein the transgene construct, when integrated into a mouse genome, undergoes trans-switching with an endogenous mouse constant region such that chimeric antibodies comprising human V regions and mouse constant regions of IgM and IgG isotype are produced in the mouse as required by the claims (see page 11, lines 4-10). Tanamachi explicitly describe transgenes which include the host murine constant region of the locus are advantageous because the expression of human Ig variable regions linked to host animal constant regions is thought to allow for improved trafficking and development of B cells and antibodies in vivo (see figure 2page 17, lines 2-32). The kappa light chain construct described in Tanamachi comprises, in 5' to 3' direction: a plurality of human VK regions, a plurality of human JK segments, a JK enhancer from a mouse host, and a CK coding region from a mouse host (see page 6, paragraph 2). Tanamachi continue to teach in a preferred embodiment that the invention provides a transgene construct which comprises, in 5' to 3' direction, a plurality of human VH regions, a plurality of human D segments, a plurality of human JH segments, a mouse J-mu enhancer, a mouse mu switch region and a mouse mu constant region, wherein the transgene contact, when integrated into a mouse genome, undergoes trans-switching with an endogenous mouse gamma constant region such that chimeric antibodies comprising human V regions and mouse constant regions (see page 5, lines 24-30). Tanamachi further discloses ligating the.. . fragment, containing the mouse J-mu enhancer, mouse mu switch region and all of the mouse mu coding regions.. .into [a restriction] site 3' of the human VDJ region (see page 5, lines 24-30, 27, lines 31 to page 28, line 1) (limitation of claims 17).
Likewise, Morrison teaches methods for producing functional immunoglobulin,” which “involve transfecting and expressing exogenous DNA coding for the heavy and light chains of immunoglobulin (Abstract). Morrison discloses that functional antibodies or immunoglobulins can be created as the expression products of chimeric fused genes. Morrison teaches these chimeric “fused genes” are derived from two different mammalian or vertebrate sources that may be produced by “joining the 5'-end of a sequence encoding the constant region in reading frame to the 3'-end of a sequence encoding the variable region.”(see col. 3, lines 17-20). Morrison provides that in designing the junction between the variable and constant regions of the fused gene, “it will usually be desirable to include all or a portion of the intron downstream from the J region.” (see col. 3, lines52-54, see fig. 1A-1B). In particular, Morrison teaches use of a chimeric J/C intron that included both mouse and human intronic DNA. This is further evidenced by the teaching of Wagner who disclosed a transgenic mouse comprises a human/mouse chimeric immunoglobulin heavy chain locus comprising a chimeric human/mouse J/C intron comprising human DNA downstream of and contiguous with said human 3' JH gene segment, which is contiguous at a junction with mouse DNA, said mouse DNA being upstream of and contiguous with mouse Eu, to wit, a human/mouse chimeric IgH locus comprising a human/mouse chimeric J/C intron, wherein said truncated mouse JC intron comprises the mouse mu enhancer (Figure 1).
Thus, one of ordinary skill in the art was aware at the time of filing of instant application that hen linking sequences encoding immunoglobulin variable gene segment and constant domains from two different mammalian sources to one another, use of a chimeric J/C intron is one of a limited number of choices for effective designs, and is a “matter of convenience.” One of ordinary skill in the art reviewing Morrison as evidenced by Wagner would have further conclude that the precise position of truncation point is not critical important. Tanamachi, Morrison and Wagner all demonstrated that functional antibodies are effectively produced by mouse cells from fused gene constructs with chimeric J/C introns.
Therefore, it also would have been obvious to one of ordinary skill in the art to substitute the human IgH/k 3 '-most J region gene segment/murine J/C intron cloning of Murphy et al/Stevens with a human IgH/k 3 '-most J region gene segment/murine J/C intron cloning of Tanamachi/Morrison as evidenced by Wagner, thus creating a human/mouse chimeric J/C intron, with a reasonable expectation of success because prior to the instant invention, one of ordinary skill in the art recognized the concept that a human/mouse chimeric J/C intron may be created so as to join human IgH V, D, and J region or human Ig VJ gene segments to a mouse J/C intron comprising the mouse Jμ enhancer, mouse switch region, and mouse IgH constant region gene segments., with a reasonable expectation of success, at the time of the instant invention, in the method of producing mouse ES cells as disclosed in Murphy and Stevens. Said modification mounting to combining prior art elements according to known methods to yield predictable results. The simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07. One of skill in the art would therefore understand from the disclosure of Murphy and the knowledge in the art that the chimeric junction should be positioned within the J-C intron, preferably at a position within the approximately 1 kb segment between the final J gene segment and the intact endogenous mouse intronic enhancer as evident from the teaching of Aguilera and Stevens (figure 2). It would have been further obvious to one of ordinary skill in the art reviewing the teaching of prior art to place chimeric junction anywhere within the intron as long as the junction does not disrupt the regulatory sequence of truncated mouse IgH/IgK intron DNA upstream of the enhancer as required by claims for initiation of recombination and expression for the hybrid IgH/IgK locus, with reasonable expectation of success. It is relevant to note that instant specification fails to disclose criticality for the presence of a chimeric J/C intron comprising human JC intronic DNA and a truncated that broadly read on few missing nucleotides from mouse JC intron. In fact, instant transgenic mouse, and the transgenic mice of Murphy/Stevens et al and Tanamachi/Morrison and Wagner all comprise the endogenous mouse Eμ enhancer (supra), which is an art-recognized element of criticality for proper expression of the human/mouse chimeric IgH/Ig antibody. One of ordinary skill in the art would recognize that there are only finite options with predictable solution when creating a chimeric human/mouse JC intron including the mouse JC intron will either be full-length or truncated in some manner so as to allow the ordinary artisan to introduce the human JH gene segments into the transgenic IgH/k locus, and the ordinary artisan could have pursued the known potential options with a reasonable expectation of success.. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 2, 12-13, 14, 16-19, 21, 24, are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (US Patent no 6596541, dated 07/22/2003) as evidenced by Murphy (2, US 8,791,323), Stevens et al (Pharma Focus Asia, 2008, 8, 72-74), Aguilera et al (EMBO 4(13B): 3689-3693, 1985) and Tanamachi et al (W02007/117410)/Morrison et al (US 5,807,715, dated 9/15/1998)/Wagner (Eur. J. Immunol. 1994, 24: 2672-2681) as evidenced by NCBI accession no L80040. 9/ 2 /2003 and further in view of Adams (Genomics. 2005 December; 86 (6):753-8). Applicants’ cancellation of claims 1, 11, renders their rejections moot
The teaching of Murphy/Stevens, Aguilera, Tanamachi, Wagner have been discussed above and relied in same manner here. The combination of reference differs from claimed invention by not explicitly disclosing (i) truncated mouse Ig JC intronic DNA upstream of said mouse enhancer comprises 782bp and (ii) the targeted insertion of large DNA in mouse and wherein said mouse enhancer comprises mouse 129Sv.
GenBank IgK JC entry for the mouse Ig kappa germline sequence that contains the J-C intronic region and flanking sequences. The annotation of the sequence indicates that the mouse JC intron spans base 2101 to 4619, and the mouse intronic enhancer in the JC intron is within bases 3888 to 4100 (annotated as the "DNase I hypersensitivity region"). Thus, GenBank IgK JC discloses that the distance between the 3' most J kappa gene segment and the mouse intronic enhancer region is less than 2 kb (i.e., 1787 bp ) (limitation of claim 13). GenBank IgK JC discloses that the span of nucleotides including the mouse intronic enhancer region (bases 3888 to 4100) and the mouse JC intron 3' of the enhancer (4101 to 4619) combined is 731 bp in length. The combination of reference differs from claimed invention by not disclosing the targeted insertion of large DNA in mouse enhancer comprises mouse 129Sv.
Prior to instant invention, maintaining the performance of the ES cell clones through multiple rounds of manipulation without the need to test the germ line potential of the ES cell line from C57BL/6N and 129 strain embryonic stem cells for mouse genetic resources were available for use. Adams et al reported that gene-targeting experiments in mice are routinely performed in 129Sv-derived embryonic stem (ES) ceil lines, which are generally considered to be more reliable at colonizing the germ line than ES cells derived from’ other strains. It is disclosed that the efficiency of recombination is affected by many factors, including the isogenicity and the length of homologous sequence of the targeting vector and the location of the target locus. Adams et al teaches double-end sequencing and mapping of 84,507 bacterial artificial chromosomes (BACs) generated from AB2.2 ES cell DNA (that have aligned these BACs against the mouse genome and displayed them on the Ensembl genome browser. Adams explicitly discloses that these BAC resources can be used for the rapid construction of targeting vectors via recombining. Furthermore, Adams show that targeting vectors containing DNA recombineered from this BAC library can be used to target genes efficiently in several 129-derived ES cell lines (See abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the cell of Murphy whose genome comprises unrearranged human lgH/Ig variable region gene segments positioned at an endogenous IgH/Ig locus upstream of a endogenous mouse constant (C) region using a mouse strain such as sv129 as suggested by Adams, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art taught ES cell clone from sv129 mouse could tolerate multiple, sequential genetic manipulation and maintain its ability to colonize the germline. One of skill in the art would have been expected to have a reasonable expectation of success in producing ES that is capable to make transgenic mouse using site specific insertion of human Ig locus in mouse endogenous Ig locus between the 3' end of JH6 gene segments and Cregions because prior art successfully reported targeted strategy to insert large sequences in mouse ES cells to produce transgenic mouse, while Murphy/Stevens taught a ES cells whose genome comprising entirely human heavy and light chain variable region loci operably linked to entirely endogenous mouse constant region loci such that the mouse produces a serum containing an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 2, 14, 17-18, 20 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Murphy et al (US Patent no 6596541, dated 07/22/2003) as evidenced by Murphy (2, US 8,791,323), Stevens et al (Pharma Focus Asia, 2008, 8, 72-74), Aguilera et al (EMBO 4(13B): 3689-3693, 1985) and Tanamachi et al (W02007/117410)/Morrison et al (US 5,807,715, dated 9/15/1998) as evidenced by Wagner (Eur. J. Immunol. 1994, 24: 2672-2681) and Adams (Genomics. 2005 December; 86 (6):753-8) as applied above and NCBI accession no NG_001019.1; 6/26/2002, IDS or X97051.1 and accession no AJ851868.3; 7/26/2007 (IDS).
The teaching of Murphy/Stevens, Aguilera, Tanamachi and Adam have been discussed above and relied in same manner here. Murphy discloses genetically modified cells as discussed supra is capable of producing-mouse from performing the equivalent variable region substitutions on the lambda and kappa light chain loci and heavy chain loci and breeding all three hybrid loci to homozygocity together in the same mouse (limitation of claims 17-18). Aguilera teaches that Ig heavy chain enhancer in the intron separating the JH region and the Cμ exons in mice (p. 3689, col. I). It is further disclosed that that the identified enhancer is typically about 1 kb or less from the 3' J gene segment (see 1 kb scale bar, figure 1A). The combination of reference differs from claimed invention by not explicitly disclosing the distance from said 3' human JH gene segment to said truncated mouse IgH JC intronic DNA is less than 2 kb.
GenBank Human IgH is the human immunoglobulin heavy chain germline sequence that contains the J-C intronic region and constant region sequence. The annotation of the sequence indicates that the distance between the 3' most 1H gene segment and the intronic enhancer region (from bp 960082 to 960908) is less than 2 kb (i.e., 826 bp ) (see page 35). GenBank Mouse IgH is the GenBank entry for the mouse immunoglobulin heavy chain germline sequence that contains the J-C intronic region and constant region sequence. The annotation of the sequence indicates that the mouse JC intron spans bases 1416058 to 1417363 (1306 bp ), and the mouse intronic enhancer in the JC intron is within bases 1416975 to 1417287 (entitled "lg enhancer region"). Thus, GenBank Mouse IgH discloses that the distance between the 3' most JH gene segment and the mouse intronic enhancer region is less than 2 kb (i.e., about 900 bp) and, in fact, the entire mouse JC intron is less than 2 kb in length (i.e., about 1300 bp).
Therefore, it would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the cell of Murphy whose genome comprises unrearranged human lgH/Ig variable region gene segments positioned at an endogenous IgH/Ig locus upstream of a endogenous mouse constant (C) region using a mouse strain such as sv129 as suggested by Adams, as instantly claimed, with a reasonable expectation of success, at the time of the instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would be motivated to do so because prior art taught that the first 12 nucleotides of the mouse (129 mouse strain) and human J/C intron sequences (immediately downstream of their respective 3' JH gene segments) are identical. Given that the first 12 nucleotides have the identical sequence. In addition, there are no structural differences in the nucleotides of a mouse and a human. Thus, there is no reason why the source of those nucleotides would have been expected to make any difference in the ability of a mouse to generate and express an immunoglobulin heavy and/or kappa chain. It is relevant to note that even if the 12 nucleotides were originally obtained from mouse or human DNA, the mouse or human DNA would not be the direct source of the DNA ultimately introduced into the J/C intron of a mouse genome. Rather, DNA from a mouse or human would have been amplified via an in vitro technique and/or bacterial culture to obtain the DNA introduced into a mouse genome, further emphasizing the technical non-criticality of the chimeric J/C intron feature. One of skill in the art would have been expected to have a reasonable expectation of success in producing ES that is capable to make transgenic mouse using site specific insertion of human Ig locus in mouse endogenous Ig locus between the 3' end of JH6 gene segments and C regions because prior art successfully reported targeted strategy to insert large sequences in mouse ES cells to produce transgenic mouse, while Murphy/Stevens taught a ES cells whose genome comprising entirely human heavy and kappa light chain variable region loci operably linked to entirely endogenous mouse constant region loci such that the mouse produces a serum containing an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Response to arguments
As an initial matter, in view of applicant’s arguments and amendments to claim 3 and claims dependent therefrom, which now requires expression of the recited chimeric Igk locus accordingly restricts the cell to a B cell, a B cell hybridoma, an ES cell and an iPS cell, obviates the basis of the rejection. Therefore, the previous rejections of claim 3 and claims dependent therefrom are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
To the extent, Applicants’ argument pertains to claims 2 and claims dependent therefrom, applicant re-iterates prior arguments on pages 21-51 that are substantially the same as discussed in previous office actions mailed on 04/09/2025 and 03/19/2026. The arguments are substantially the same as those addressed in the prior office actions mailed on 04/09/2025 and 03/19/2026 and incorporated herein. To the extent that Applicants’ arguments are pertinent to new arguments and rebuttal to the previous office action, they are addressed as follows:
Applicants disagree with the rejection arguing Tanamachi does not teach a chimeric immunoglobulin kappa locus that comprises truncated mouse Igk JC intronic DNA comprising an Ig kappa enhancer, as required by the instant claims. Applicant further traverses that "Tanamachi et al disclosed the successful reduction to practice of constructing a chimeric human/mouse IgH locus comprising a chimeric human/mouse JC intron, whereby the mouse JC intron is a truncated mouse JC intron". Applicant notes the design choice presented by Morrison relates to a fusion protein in essence in a cell as opposed to a mouse comprising antibody locus comprising a multitude of unrearranged variable gene segments. Morrison teaches nucleic acid encoding a fusion protein comprising a single rearranged VJ variable region and a constant region with an intervening space between them. Obviously the JC intron is not playing a role in rearrangement of V and J gene segments and/or selection of individual gene segments thereof, in nucleic acid encoding this single fusion protein. Clearly, Morrison doesn't address how their design choice relates to the ability of gene segments of an antibody locus to rearrange, a critical component of the instant claims. Thus, in contrast to the unrearranged locus encompassing multiple V region gene segments of the instant claims and that of Tanamachi, Morrison teaches nucleic acid encoding a fusion protein comprising a single rearranged VJ variable region and a constant region with an intervening space between them. Obviously, the JC intron is not playing a role in rearrangement of V and J gene segments and/or selection of individual gene segments thereof, in nucleic acid encoding this single fusion protein. Applicants fail to see the ability to extrapolate any role of the JC intron from Morrison's nucleic acid encoding this single fusion protein to the instantly recited loci encoding unrearranged V and J gene segments. he claims recite a truncated mouse JC intron of an unrearranged kappa locus integrated at the respective endogenous Ig locus. Applicant notes that the chimeric Igk locus of the mouse taught by Murphy which comprises the full mouse JC intron, differs from the chimeric Igk locus of the instantly recited germ line chimeric Igk locus which comprises a truncated mouse JC intron. Applicants’ arguments have been fully considered but are not found persuasive.
In response to applicants’ argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., design choice relates to the ability of gene segments of an antibody locus to rearrange, a critical component of the instant claims) 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 view of applicants’ amendments to claims that require cell capable of undergoing rearrangement of said human unrearranged human kappa V and J gene segments to form and express said human kappa VJ gene operatively joined to a mouse kappa C gene segment, previous rejection of claims 3 and claims dependent therefrom have been withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. However, rejection is maintained for claim 2 and claims dependent therefrom for the reasons of record. None of the rejected claims require ability of gene segments of an antibody locus to rearrange.
In response it should be noted while Tanamachi does not teach a chimeric immunoglobulin kappa locus as required by the claims 2, however, Tanamachi is still relevant to the similar concept for a heavy chain Ig locus comprises an unrearranged human heavy chain variable region gene segments comprising human IgH V gene segments, human D gene segments and human IgH J gene segments, truncated human IgH JC intronic DNA, truncated mouse IgH JC intronic DNA, said enhancer and said heavy chain constant region comprising said mouse heavy chain constant gene segment (see claim 18). Tanamachi teaches construction steps by which the human VDJ region gene segments are cloned to the mouse Jμ enhancer, mouse μ switch regions, and all of the mouse μ coding regions (pages 26-28). Tanamachi et al do not disclose that isolated fragment comprises the complete or entire mouse J/C intron. Rather, the 5' NgoMIV restriction site appears to be 5' adjacent to the mouse J μ enhancer, not immediately adjacent to the 3' -most J gene segment (Figure 1). Thus, the ordinary artisan would understand the construct of Tanamachi et al to comprise human IgH V, D, and J gene segments, and a human/mouse chimeric J/C intron comprising a portion of the human J/C intron "5' of the human J μ enhancer" (page 26, line 32) and a truncated mouse J/C intron comprising the mouse J μ enhancer, mouse μ switch regions, and all of the mouse μ coding regions. This is further evident from Bradley’s declaration who reported Tanamachi. contains most of, but not the entire mouse J/C intron and also contains 456bp of human DNA downstream of 3’end of human JH6 (see fig. 1) (see section 4 and 5 of Bradley’s declaration filed on 8/23/2021).
In response to applicant’s argument that Murphy teaching of a retaining entire mouse JC intron is inconsistent with the teaching of other prior art (Tanamachi or Morrison), it should be noted that Murphy neither forbids, discourages, or otherwise discredits the use of a chimeric human/mouse JC intron, whereby the mouse JC intron is a truncated mouse JC intron. Rather, Murphy et al merely discloses the cloning step they performed. Tanamachi et al disclosed the successful reduction to practice of constructing a chimeric human/mouse IgH locus comprising a chimeric human/mouse JC intron, whereby the mouse JC intron is a truncated mouse JC intron. MPEP 2141 states “the focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the relevant time, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. “
In view of foregoing prior art, one of ordinary skill in the art would have recognized the concept that a human/mouse chimeric J/C intron may be created so as to join human IgH/L gene segments to a mouse J/C intron comprising the mouse Jμ enhancer, mouse μ switch region, and mouse IgH/L constant region gene segments, whereby the mouse JC intron may be entirely present (Murphy et al) or truncated (Tanamachi et al or Morrison). The simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07. Further, the "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art.
In response to applicant’s argument that Morrison pertains to a nucleic acid encoding a fusion protein comprising a single rearranged VJ variable region and a constant region with an intervening space between them and JC intron is not playing a role in rearrangement of V and J gene segments and/or selection of individual gene segments thereof, in nucleic acid encoding this single fusion protein, it should be noted that Morrison is applied as an alternative reference to Tanamachi that further establishes the fact that chimeric JC introns were well known to a person of ordinary skill in the art and would have understood it be a convenient design choice to produce cells disclosed in Murphy.
It is relevant to note that Morrison is specifically directed to a method for producing functional immunoglobulin, which “involve transfecting and expressing exogenous DNA coding for the heavy and light chains of immunoglobulin by creating the expression product of a chimeric fused gene (see abstract). Morrison emphasized that the“fused genes” are derived from two different mammalian or vertebrate sources that may be produced by “joining the 5'-end of a sequence encoding the constant region in reading frame to the 3'-end of a sequence encoding the variable region.” (col. 3:lines 17-20). Morrison states “it will usually be desirable to include all or a portion of the intron downstream from the J region.” (col. 3: lines 52-54) (emphasis added). In particular, Morrison explains design choices and chose to use a chimeric J/C intron that included both mice and human intronic DNA (see fig. 1A).
Thus, contrary to applicant’s argument, Morrison provide proof of concept by stating when linking sequences encoding immunoglobulin variable gene segment and constant domains from two different mammalian sources to one another, use of a chimeric J/C intron is one of a limited number of choices for effective designs and is a “matter of convenience. In the instant case, all the prior art references emphasize maintaining the mouse enhancer in the J/C intron of their chimeric immunoglobulin constructs. Morrison expressly discloses that joining human and mouse DNA within the J/C intron both preserves the intronic enhancer, as Murphy and Morrison teach, and is otherwise “a matter of convenience.” (see col. 3: lines 52-62). Therefore, joining the human and mouse DNA within the J/C intron would result in a chimeric J/C intron. Morrison exemplified antibody production in mouse cells that utilize constructs that include a chimeric J/C intron. (see col. 9: lines 44-46). Absent any requirement of any specific phenotype
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants’ arguments are not compelling and do not overcome the rejection of record.
Withdrawn -Double Patenting
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7-10, 15 of copending Application No. 17878628and Tanamachi et al (W02007/117410). The rejection is withdrawn as ‘628 is no longer pending application and therefore, previous rejection of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18166813 and Tanamachi et al (W02007/117410). The rejection is withdrawn as ‘813 is no longer pending application and therefore, previous rejection of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained & New -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 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of USP 11399522 and Tanamachi et al (W02007/117410) for the reasons of record. Although the conflicting claims are not identical, they are not patentably distinct from each other because claims in both applications are directed to overlapping subject matter.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of USP. 10966412 and Tanamachi et al (W02007/117410) for the reasons of record. Although the conflicting claims are not identical, they are not patentably distinct from each other because claims in both applications are directed to overlapping subject matter. The method of ‘809 encmpasses the isolated mouse cell of the instant application.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-25 of USP 10064398 and Tanamachi et al (W02007/117410) for the reasons of record.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of USP 11812731 (14056700) and Tanamachi et al (W02007/117410) for the reasons of record.
Claims 2-3, 5-6, 12-24, 26, 32-35, 37, 39 and 40 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of US Patent no 11606941 (Application No. 15232122) and Tanamachi et al (W02007/117410) for the reasons of record. Although the claims at issue are not identical, they are not patentably distinct from each other. '941 claims encompass use of a transgenic mouse whose genome is structurally similar to one claimed in the instant application. The ‘941 differs from claimed invention by not disclosing isolated mouse cell or a B cell or hybridoma derived the mouse of ‘628. Tanamachi cure the deficiency by teaching isolating B-cell (see page 19, line 32) or hybridoma (see page 20, line 1) from a mouse prepared from genetically modified ES cells. Tanamachi disclose that the mouse of the invention comprises, in 5' to 3' direction, a plurality of human Vh regions, a plurality of human D segments, a plurality of human JH segments, a mouse J-mu enhancer, a mouse p switch region and a mouse p constant region, wherein the transgene construct, when integrated into a mouse genome, undergoes trans-switching with an endogenous mouse constant region such that chimeric antibodies comprising human V regions and mouse constant regions of IgM and IgG isotype are produced in the mouse as required by the claims (see page 11, lines 4-10). Therefore, it would have been obvious for one of ordinary skill in the art to isolate B-cell or prepare hybridoma from the mouse disclosed in ‘941.
Response to argument
While Applicant has requested that the rejection be held in abeyance until allowable subject matter can be identified, a request of abeyance does not overcome or address an issue of obvious double patenting between claims in the instant case and US patent and US Patent application. Thus, the rejection is maintained.
Conclusion
No claims allowed.
Claims 3, 5, 26, 32-35, 37, 39 and 40 are free of prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sullivan, P. M., et al. Journal of Biological Chemistry 272.29: 17972-17980, 1997 teaches mice were engineered with a targeting construct containing a chimeric intron: "the 3' part of intron 1 (723 base pairs), exons 2-4 of the human APOE3 gene, and 1.5 kb of 3 '-flanking DNA" and "[a] 5.3-kb EcoRI-Sacl strain 129 mouse genomic fragment containing sequences ... the 5' part of intron 1 (376 base pairs) was inserted 5' to the human APOE3 fragment" (p. 17973, left col).
Lefranc, Marie-Paule, and Gerard Lefranc. The Immunoglobulin Facts Book. l st Ed. pp. 45-68. London: Academic Press, 2001 teaches the human IgK locus spans approximately 1800kb, including a span of 800 kb separating the proximal and distalclusters. As such, each cluster spans about 400-500kb of the locus (see figure 4).
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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