DETAILED ACTION
Claims 29-30, 36, 42, 48, 50, 55, 59, 65-66, 68, 77-81, 101 and 114-115 are currently pending and under examination in this 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 statements (IDS) submitted on 12/16/24, 3/18/25, 7/2/25, and 12/15/25 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner and initialed and signed copies of the 1449s are attached to this action.
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 48, 55, and 59 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 48 depends on claim 29 and lacks antecedent basis for the “the exogenous nucleic acid sequence”. Claim 29 does not refer to the presence of any exogenous nucleic acid sequence. As such, proper antecedent basis is lacking for this limitation.
Claim 55 recites a method genetically modifying a non-human animal, wherein step (c) recites that chimeric non-human animal is obtained. However, in steps (d), and (f), the claims recites “the chimeric non-human”, not a chimeric non-human animal, and further refer to wild-type non-human, and a founder non-human. A chimeric “non-human” is not equivalent in scope with “non-human animal” as the non-human is not limited to an animal. Thus, the metes and bounds of the claim are confusing. Further, there is no antecedent basis for “the chimeric non-human” in step (d). Likewise, the scope of “wild-type non-human” and “founder non-human” is confusing as the preamble refers to a non-human animal not any type of non-human organism. Thus, the metes and bounds of the claim as a whole cannot be determined. Claim 59 depends on claim 55 is thus included in this rejection.
In the interests of compact prosecution, claim 55 has been interpreted as encompassing crossing a chimeric non-human animal with a wild type animal, and further encompassing identifying a founder non-human animal.
Claim 59 is further indefinite in that the preamble recites, “ a method of producing a single domain antibody (sdAb) identified from the engineered non-human animal of claim 55”. It is first noted that claim 55 is drawn to a genetically modified non-human animal, not an “engineered” non-human animal. As such, “the engineered non-human animal of claim 55” lacks antecedent basis. Further, as not such engineered non-human animal is recited in claim 55, the metes and bounds of such an animal cannot be determined. In addition, as the method of claim 55 does not identify any nucleic acids encoding a heavy chain variable domain in said genetically modified non-human animal, it is unclear how the phrase “identified from the engineered non-human animal of claim 55” relates to the active steps of claim 59 which simply recite expressing a nucleic acid encoding a heavy chain variable domain in a cell and isolating the heavy chin therefrom. The steps recited in claim 59 do not actually include identifying or obtaining any nucleic acid from any non-human animal. Thus, the metes and bounds of the nucleic acid encoding a heavy chain variable domain to be expressed in the cell cannot be determined.
In the interests of compact prosecution, the nucleic acid encoding a heavy chain variable domain to be expressed in the cell has been given its broadest reasonable interpretation as encompassing any nucleic acid encoding a heavy chain variable domain that can produce single domain antibody.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 29, 36, and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren et al. (2004) Genomics, Vol. 84, 686-695.
Ren et al. teaches the deletion of all of the endogenous heavy chain constant region genes in mice, which includes all eight C-region genes including Cm, Cd, Cg3, Cg1, Cg2b, Cg2a, Ce, and Ca (Ren et al., pages 686-687 and Figure 1). Ren et al. teaches the deletion of a 200 kb region of the heavy chain locus comprising the eight constant region genes in mouse embryonic stem cells and using the modified mouse embryonic stem cells to generate heterozygous mice and breeding the heterozygous mice to generate homozygous mice (Ren et al., pages 687-688). No other genetic modification is made to mouse, which therefore still contains the endogenous heavy chain variable region V, D, and J gene segments. Thus, by teaching all the limitations of the claims as written, Ren et al. anticipates the instant invention as claimed.
Claims 29, 36, and 50 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lutz et al. (1998) Nature, Vol. 393, 797-801.
Lutz et al. teaches transgenic mice with a deletion of the entire mouse heavy chain gene, including Cm1, Cm1, Cm1, Cm1, M1, and M2, at the endogenous heavy chain locus without modification of the endogenous variable region V, D, and J gene segments (Lutz et al., pages 798 and Figure 1). Lutz et al. teaches deletion of the Cm gene in mouse embryonic stem cells followed by injection of the ES cells into blastocysts and reimplantation in the uteri of pseudopregnant female mice where mice with germline transmission were identified and use to breed homozygous mice (Lutz et al., page 800). Thus, by teaching all the limitations of the claims as written, Lutz et al. anticipates the instant invention as claimed.
Claims 29-30, 36, 42, 50, 59, 65-66, 68, 77-81, and 115 are rejected under 35 U.S.C. 102(a)(1) as anticipated by WO 2010/109165 (March 22, 2010), hereafter referred to as Janssens et al.
Janssens et al. teaches, “a heterologous heavy chain-only locus comprising one or more V gene segments according to the invention, one or more D gene segments according to the invention, one or more J gene segments according to the invention and one or more constant effector region gene segments ... wherein the gene segments are arranged such that a V, a D and J gene segment and a constant region gene segment can recombine to produce a rearranged gene encoding a high affinity, antigen-specific, soluble heavy chain-only antibody according to the invention” (Janssens et al., page 14, lines 28 to page 15, line 2). Janssens et al. teaches that the V, D, and J gene segments can be any species but are preferably human (Janssens et al., page 30, lines 31-32) and, when recombined, undergoes affinity maturation (Janssens et al., page 13, lines 27-29). Janssens et al. teaches that the heavy chain locus comprises 2 or more VH gene segments, from two to forty or more DH segments and two to twenty JH segments (Janssens et al., pages 29-30). Janssens et al. also teaches that the heavy chain locus such as the endogenous heavy chain locus includes “a heavy chain constant effector region comprising one or more exons but not a functional CH1 exon” (Janssens et al., page 29, lines 25-31, see also page 15, lines 18-20, and page 31, lines 12-14, and page 33). More specifically, Janssens et al. teaches that each heavy chain constant region essentially comprises at least one heavy chain constant region gene, which is expressed without a functional CH1 domain so that generation of heavy chain-only antibody can occur (Janssens et al., page 32). Janssens et al. also teaches that the heavy chain constant region may also comprise one or more additional heavy chain constant region exons, which are selected from the group consisting of Ca, Cg1-4, Cm, and Ce, where the heavy chain constant region gene segments are selected depending on the preferred class or mixture of antibody classes required (Janssens et al., page 32). Janssens et al. further teaches an embodiment where the heterologous heavy chain locus is Cm- and Cd-deficient (Janssens et al., page 32 and Figure 1). In addition, Janssens et al. teaches that the expression of all or part of a heterologous heavy chain Cg locus devoid of CH1 will produce some or all IgG isotypes, dependent on the IgG1, IgG2, IgG3 and IgG4 isotypes present in the heterologous IgG locus; or alternatively, selected mixtures of antibodies may be obtained, where for example IgA may be obtained when the heavy chain constant region comprises a Ca (Janssens et al., page 32). Note that while Janssens et al. does not explicitly state that the constant region CH2 and CH3 regions are present in the constant region genes lacking CH1, such is inherent to the targeted deletion of the CH1 domain taught by Janssens et al. Janssens et al. provides two examples of modified heavy chain loci. In one example, the loci comprises human V, D, and J gene segments, and only a Cg2 gene lacking the CH1 domain and a Cg3 gene lacking the CH1 domain with no Cm, Cd, Cg1, Ce, or Ca gene sequence (Janssens et al. Figure 1). In the second example, the locus comprises human V, D, and J, gene segments, and four constant region genes which lack CH1-Cm, Cg3, Cg1, Cg2, and no Cd, Ce, and Ca constant region sequence (Janssens et al., Figure 1). Janssens et al. further teaches transgenic non-human animals comprising the heterologous heavy chain-only antibody loci, including transgenic non-human animals in which the endogenous kappa and lambda light chain genes are functionally silenced or deleted (Janssens et al., page 15, lines 16-18 and page 32, lines 21-28). Janssens et al. teaches that homologous recombination in ES cells can be used to eliminate CH1 functionality and modify the heavy chain locus (Janssens et al., pages 32-33). Methods of producing a heavy chain-only antibody using the transgenic non-human animals are also disclosed in Janssens et al., including methods that include immunizing the transgenic animal, isolating nucleic acid sequences encoding heavy chain-only antibodies and/or soluble VH domains from B-cells of the transgenic animal following antigen challenge, and using the nucleic acid sequences isolated to produce soluble VH domain heavy chain-only antibodies, soluble bi-specific/bi-functional VH domain complexes, or soluble VH domain polyproteins using recombinant DNA techniques familiar to those skilled in the art (Janssens et al., page 33, lines 19-32, and page 34, lines 1-3). Thus, by teaching multiple embodiments of the claims, including embodiments where the as written, Janssens et al. anticipates that the instant invention as claimed.
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 29-30, 36, 42, 48, 50, 55, 59, 65-66, 68, 77-81, 101 and 114-115are rejected under 35 U.S.C. 103 as being unpatentable over WO 2010/109165 (March 22, 2010), hereafter referred to as Janssens et al., in view of Lutz et al. (1998) Nature, Vol. 393, 797-801, Ma et al. (2021) Introduction to Antibody Engineering, Chapter 5, pages 97-127, published online December 1, 2020, and MacDonald et al. (2014) PNAS, Vol. 111(14), 5147-5152.
Janssens et al. teaches, “a heterologous heavy chain-only locus comprising one or more V gene segments according to the invention, one or more D gene segments according to the invention, one or more J gene segments according to the invention and one or more constant effector region gene segments ... wherein the gene segments are arranged such that a V, a D and J gene segment and a constant region gene segment can recombine to produce a rearranged gene encoding a high affinity, antigen-specific, soluble heavy chain-only antibody according to the invention” (Janssens et al., page 14, lines 28 to page 15, line 2). Janssens et al. teaches that the V, D, and J gene segments can be any species but are preferably human (Janssens et al., page 30, lines 31-32) and, when recombined, undergoes affinity maturation (Janssens et al., page 13, lines 27-29). Janssens et al. teaches that the heavy chain locus comprises 2 or more VH gene segments, from two to forty or more DH segments and two to twenty JH segments (Janssens et al., pages 29-30). Janssens et al. also teaches that the heavy chain locus such as the endogenous heavy chain locus includes “a heavy chain constant effector region comprising one or more exons but not a functional CH1 exon” (Janssens et al., page 29, lines 25-31, see also page 15, lines 18-20, and page 31, lines 12-14, and page 33). More specifically, Janssens et al. teaches that each heavy chain constant region essentially comprises at least one heavy chain constant region gene, which is expressed without a functional CH1 domain so that generation of heavy chain-only antibody can occur (Janssens et al., page 32). Janssens et al. also teaches that the heavy chain constant region may also comprise one or more additional heavy chain constant region exons, which are selected from the group consisting of Ca, Cg1-4, Cm, and Ce, where the heavy chain constant region gene segments are selected depending on the preferred class or mixture of antibody classes required (Janssens et al., page 32). Janssens et al. further teaches an embodiment where the heterologous heavy chain locus is Cm- and Cd-deficient (Janssens et al., page 32 and Figure 1). In addition, Janssens et al. teaches that the expression of all or part of a heterologous heavy chain Cg locus devoid of CH1 will produce some or all IgG isotypes, dependent on the IgG1, IgG2, IgG3 and IgG4 isotypes present in the heterologous IgG locus; or alternatively, selected mixtures of antibodies may be obtained, where for example IgA may be obtained when the heavy chain constant region comprises a Ca (Janssens et al., page 32). Note that while Janssens et al. does not explicitly state that the constant region CH2 and CH3 regions are present in the constant region genes lacking CH1, such is inherent to the targeted deletion of the CH1 domain taught by Janssens et al. Janssens et al. provides two examples of modified heavy chain loci. In one example, the loci comprises human V, D, and J gene segments, and only a Cg2 gene lacking the CH1 domain and a Cg3 gene lacking the CH1 domain with no Cm, Cd, Cg1, Ce, or Ca gene sequence (Janssens et al. Figure 1). In the second example, the locus comprises human V, D, and J, gene segments, and four constant region genes which lack CH1-Cm, Cg3, Cg1, Cg2, and no Cd, Ce, and Ca constant region sequence (Janssens et al., Figure 1). Janssens et al. further teaches transgenic non-human animals comprising the heterologous heavy chain-only antibody loci, including transgenic non-human animals in which the endogenous kappa and lambda light chain genes are functionally silenced or deleted (Janssens et al., page 15, lines 16-18 and page 32, lines 21-28). Janssens et al. teaches that homologous recombination in ES cells can be used to eliminate CH1 functionality and modify the heavy chain locus (Janssens et al., pages 32-33). Methods of producing a heavy chain-only antibody using the transgenic non-human animals are also disclosed in Janssens et al., including methods that include immunizing the transgenic animal, isolating nucleic acid sequences encoding heavy chain-only antibodies and/or soluble VH domains from B-cells of the transgenic animal following antigen challenge, and using the nucleic acid sequences isolated to produce soluble VH domain heavy chain-only antibodies, soluble bi-specific/bi-functional VH domain complexes, or soluble VH domain polyproteins using recombinant DNA techniques familiar to those skilled in the art (Janssens et al., page 33, lines 19-32, and page 34, lines 1-3).
Janssens et al., while teaching to use homologous recombination in ES cells to modify the endogenous heavy chain locus, does not provide additional teachings regarding how to generate a transgenic mouse from said ES cells. Lutz et al. supplements Janssens et al. by teaching transgenic mice with a deletion of the entire mouse heavy chain Cm gene, including Cm1, Cm1, Cm1, Cm1, M1, and M2, at the endogenous heavy chain locus without modification of the endogenous variable region V, D, and J gene segments (Lutz et al., pages 798 and Figure 1). Lutz et al. teaches deletion of the Cm gene in mouse embryonic stem cells followed by injection of the ES cells into blastocysts and reimplantation in the uteri of pseudopregnant female mice where mice with germline transmission were identified and use to breed homozygous mice (Lutz et al., page 800). Thus, based on the teachings of Janssens et al. to make modifications in ES cell in order to generate a transgenic mouse or other non-human animal, and the specific teachings of Lutz et al. for methods of introducing modifications to the endogenous mouse heavy chain locus, and specifically the constant region genes, in mouse ES cells, and for specific steps to use such ES cells to generate both heterozygous and homozygous mice, it would have been prima facie obvious to the skilled artisan at the time of filing to make the transgenic mice taught by Janssens et al. using the methods taught by Lutz et al. with a reasonable expectation of success.
Janssens et al., while teaching to introduce human VH, DH, and JH gene segments into the mouse genome, and particularly 2 or more human VH gene segments, does not teach to introduce at least 65 VH gene segments, or at least 126 VH gene segments into the mouse genome. However, at the time of filing, Ma et al. teaches that as many as 147 VH gene segments had been identified in the human genome, and that multiple transgenic mice have been produced with increasing numbers of introduced human VH gene segments over the years, starting with the introduction of 1 or 2 VH gene segments in the late 1980s to early 1990s up to approximately 80 human VH gene segments in the 2010s (Ma et al., pages 100, 105, and 115). Ma et al. in particular teaches a number of specific transgenic mice whose endogenous heavy chain locus have been modified to replace the mouse VH, DH, and JH gene segments with human VH, DH, and JH gene segments operatively liked to the endogenous mouse constant region (Ma et al., Figure 5.2, and pages 115-117). The Velocimmune mouse for example comprises 80 human VH, 27 DH, and 6 JH segments (Ma et al, page 116). MacDonald et al. further supplements Janssens et al. and Ma et al. by teaching a specific methodology of sequentially adding additional human genomic sequence comprising additional VH gene segments to the mouse endogenous heavy chain locus which was used to make the Velocimmune mouse (MacDonald et al., Figure 1). The methodology taught by MacDonald successfully replaced the mouse VH gene segments with 80 human VH gene segments where each sequential modification added between approximately 90-210 kb of human genomic sequence comprising multiple additional VHs (MacDonald et al., Figure 1). MacDonald et al. teaches that their precision megabase insertion of human VH, DH, and JH genomic sequence replacing the endogenous mouse VH, DH, and JH gene segments, and in operative linkage to endogenous mouse constant regions genes, created mice with superior function in generating humanized antibodies compared to previous generations of humanized antibody mice (MacDonald et al., page 5151). Therefore, in view of the teachings of Ma et al. that there are approximately 147 VH gene segments in the human heavy chain locus, and that progression of the state of the art in generating humanized antibodies in transgenic mouse involved increasing the number of human VH gene segments in the mouse heavy chain locus, the teachings of MacDonald for a specific and successful methodology to sequentially and precisely add additional VH genomic sequence encoding additional human VH gene segments to an endogenous heavy chain locus in a mouse, and the teachings of MacDonald that increasing the number of human VH segments to 80 VH, replacing the endogenous VH gene segments in the transgenic mouse, generated a mouse with superior function compared to previous generations of humanized mice, it would have been prima facie obvious to the skilled artisan at the time of filing to generate transgenic mice expressing heavy chain only antibodies according to Janssens et al. where the number of inserted human VH gene is at least 80 up to 147 VH gene segments, the complete number of known VH gene segments, with reasonable expectation of success in expressing chimeric heavy chain only antibodies in the mice.
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 29-30, 36, 42, 48, 50, 55, 59, 65-66, 68, 77-81, 101 and 114-115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 15-16, and 24-40 of copending Application No. 19/128,438, hereafter referred to as the ‘438 application, either alone or in view of WO 2010/109165 (March 22, 2010), hereafter referred to as Janssens et al., Lutz et al. (1998) Nature, Vol. 393, 797-801, Ma et al. (2021) Introduction to Antibody Engineering, Chapter 5, pages 97-127, published online December 1, 2020, and MacDonald et al. (2014) PNAS, Vol. 111(14), 5147-5152.
The ‘438 application claims are not identical but overlap substantially with the instant claims with regards to modifications to the endogenous constant region genes, including deletions of particular constant regions, and modifications to certain constant region genes to specifically delete the CH1 domain, in a genetically modified non-human animal. However, the ‘438 application claims broadly encompass but do not specifically recite the further inclusion of human VH, DH, and JH gene segments at the endogenous locus, specific numbers of human VH, DH, or JH gene segments, or the use of ES cells to make the genetically modified non-human animals.
Janssens et al. supplements the ‘438 application claims by teaching, “a heterologous heavy chain-only locus comprising one or more V gene segments according to the invention, one or more D gene segments according to the invention, one or more J gene segments according to the invention and one or more constant effector region gene segments ... wherein the gene segments are arranged such that a V, a D and J gene segment and a constant region gene segment can recombine to produce a rearranged gene encoding a high affinity, antigen-specific, soluble heavy chain-only antibody according to the invention” (Janssens et al., page 14, lines 28 to page 15, line 2). Janssens et al. teaches that the V, D, and J gene segments can be any species but are preferably human (Janssens et al., page 30, lines 31-32) and, when recombined, undergoes affinity maturation (Janssens et al., page 13, lines 27-29). Janssens et al. teaches that the heavy chain locus comprises 2 or more VH gene segments, from two to forty or more DH segments and two to twenty JH segments (Janssens et al., pages 29-30). Janssens et al. also teaches that the heavy chain locus such as the endogenous heavy chain locus includes “a heavy chain constant effector region comprising one or more exons but not a functional CH1 exon” (Janssens et al., page 29, lines 25-31, see also page 15, lines 18-20, and page 31, lines 12-14, and page 33). More specifically, Janssens et al. teaches that each heavy chain constant region essentially comprises at least one heavy chain constant region gene, which is expressed without a functional CH1 domain so that generation of heavy chain-only antibody can occur (Janssens et al., page 32). Janssens et al. also teaches that the heavy chain constant region may also comprise one or more additional heavy chain constant region exons, which are selected from the group consisting of Ca, Cg1-4, Cm, and Ce, where the heavy chain constant region gene segments are selected depending on the preferred class or mixture of antibody classes required (Janssens et al., page 32). Janssens et al. further teaches an embodiment where the heterologous heavy chain locus is Cm- and Cd-deficient (Janssens et al., page 32 and Figure 1). In addition, Janssens et al. teaches that the expression of all or part of a heterologous heavy chain Cg locus devoid of CH1 will produce some or all IgG isotypes, dependent on the IgG1, IgG2, IgG3 and IgG4 isotypes present in the heterologous IgG locus; or alternatively, selected mixtures of antibodies may be obtained, where for example IgA may be obtained when the heavy chain constant region comprises a Ca (Janssens et al., page 32). Note that while Janssens et al. does not explicitly state that the constant region CH2 and CH3 regions are present in the constant region genes lacking CH1, such is inherent to the targeted deletion of the CH1 domain taught by Janssens et al. Janssens et al. provides two examples of modified heavy chain loci. In one example, the loci comprises human V, D, and J gene segments, and only a Cg2 gene lacking the CH1 domain and a Cg3 gene lacking the CH1 domain with no Cm, Cd, Cg1, Ce, or Ca gene sequence (Janssens et al. Figure 1). In the second example, the locus comprises human V, D, and J, gene segments, and four constant region genes which lack CH1-Cm, Cg3, Cg1, Cg2, and no Cd, Ce, and Ca constant region sequence (Janssens et al., Figure 1). Janssens et al. further teaches transgenic non-human animals comprising the heterologous heavy chain-only antibody loci, including transgenic non-human animals in which the endogenous kappa and lambda light chain genes are functionally silenced or deleted (Janssens et al., page 15, lines 16-18 and page 32, lines 21-28). Janssens et al. teaches that homologous recombination in ES cells can be used to eliminate CH1 functionality and modify the heavy chain locus (Janssens et al., pages 32-33). Methods of producing a heavy chain-only antibody using the transgenic non-human animals are also disclosed in Janssens et al., including methods that include immunizing the transgenic animal, isolating nucleic acid sequences encoding heavy chain-only antibodies and/or soluble VH domains from B-cells of the transgenic animal following antigen challenge, and using the nucleic acid sequences isolated to produce soluble VH domain heavy chain-only antibodies, soluble bi-specific/bi-functional VH domain complexes, or soluble VH domain polyproteins using recombinant DNA techniques familiar to those skilled in the art (Janssens et al., page 33, lines 19-32, and page 34, lines 1-3). Thus, based on the substantial teachings in Janssens et al. for including human VH, DH, and JH gene segments at the endogenous heavy chain locus in a transgenic mouse, it would have been obvious to the skilled artisan at the time of filing to further include human VH, DH, and JH gene segments in the endogenous heavy chain locus comprising modified constant regions gene of the non-human animal set forth in the ‘438 application claims with a reasonable expectation of success.
Janssens et al., while teaching to use homologous recombination in ES cells to modify the endogenous heavy chain locus, does not provide additional teachings regarding how to generate a transgenic mouse from said ES cells. Lutz et al. supplements Janssens et al. by teaching transgenic mice with a deletion of the entire mouse heavy chain Cm gene, including Cm1, Cm1, Cm1, Cm1, M1, and M2, at the endogenous heavy chain locus without modification of the endogenous variable region V, D, and J gene segments (Lutz et al., pages 798 and Figure 1). Lutz et al. teaches deletion of the Cm gene in mouse embryonic stem cells followed by injection of the ES cells into blastocysts and reimplantation in the uteri of pseudopregnant female mice where mice with germline transmission were identified and use to breed homozygous mice (Lutz et al., page 800). Thus, based on the teachings of Janssens et al. to make modifications in ES cell in order to generate a transgenic mouse or other non-human animal, and the specific teachings of Lutz et al. for methods of introducing modifications to the endogenous mouse heavy chain locus, and specifically the constant region genes, in mouse ES cells, and for specific steps to use such ES cells to generate both heterozygous and homozygous mice, it would have been obvious to the skilled artisan at the time of filing to make the genetically modified transgenic animals as set forth in the ‘438 application claims using the methods taught by Lutz et al. with a reasonable expectation of success.
Janssens et al., while teaching to introduce human VH, DH, and JH gene segments into the mouse genome, and particularly 2 or more human VH gene segments, does not teach to introduce at least 65 VH gene segments, or at least 126 VH gene segments into the mouse genome. However, at the time of filing, Ma et al. teaches that as many as 147 VH gene segments had been identified in the human genome, and that multiple transgenic mice have been produced with increasing numbers of introduced human VH gene segments over the years, starting with the introduction of 1 or 2 VH gene segments in the late 1980s to early 1990s up to approximately 80 human VH gene segments in the 2010s (Ma et al., pages 100, 105, and 115). Ma et al. in particular teaches a number of specific transgenic mice whose endogenous heavy chain locus have been modified to replace the mouse VH, DH, and JH gene segments with human VH, DH, and JH gene segments operatively liked to the endogenous mouse constant region (Ma et al., Figure 5.2, and pages 115-117). The Velocimmune mouse for example comprises 80 human VH, 27 DH, and 6 JH segments (Ma et al, page 116). MacDonald et al. further supplements Janssens et al. and Ma et al. by teaching a specific methodology of sequentially adding additional human genomic sequence comprising additional VH gene segments to the mouse endogenous heavy chain locus which was used to make the Velocimmune mouse (MacDonald et al., Figure 1). The methodology taught by MacDonald successfully replaced the mouse VH gene segments with 80 human VH gene segments where each sequential modification added between approximately 90-210 kb of human genomic sequence comprising multiple additional VHs (MacDonald et al., Figure 1). MacDonald et al. teaches that their precision megabase insertion of human VH, DH, and JH genomic sequence replacing the endogenous mouse VH, DH, and JH gene segments, and in operative linkage to endogenous mouse constant regions genes, created mice with superior function in generating humanized antibodies compared to previous generations of humanized antibody mice (MacDonald et al., page 5151). Therefore, in view of the teachings of Jenssens et al. to include human VH, DH, and JH gene segments in the endogenous heavy chain locus which further comprises modified constant region genes, the teachings of Ma et al. that there are approximately 147 VH gene segments in the human heavy chain locus, and that progression of the state of the art in generating humanized antibodies in transgenic mouse involved increasing the number of human VH gene segments in the mouse heavy chain locus, the teachings of MacDonald for a specific and successful methodology to sequentially and precisely add additional VH genomic sequence encoding additional human VH gene segments to an endogenous heavy chain locus in a mouse, and the teachings of MacDonald that increasing the number of human VH segments to 80 VH, replacing the endogenous VH gene segments in the transgenic mouse, generated a mouse with superior function compared to previous generations of humanized mice, it would have been obvious to the skilled artisan at the time of filing to generate transgenic mice expressing heavy chain only antibodies according to ‘438 application claims where the number of inserted human VH gene is at least 80 up to 147 VH gene segments, the complete number of known VH gene segments, with reasonable expectation of success in expressing chimeric heavy chain only antibodies in the mice.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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