Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-20 have been canceled. Claims 21-32 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 27-32, in the reply filed on 8-6-26 is acknowledged.
Upon reconsideration, the restriction has been withdrawn.
Claims 21-32 are under consideration.
Claim Rejections - 35 USC § 112
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.
Written Description
Claims 21-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification lacks written description for making any genetically modified mouse as broadly encompassed by claims 21 and 27 other than a genetically modified mouse whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain.
Claims 21 is drawn to making a mouse whose germline genome comprises an engineered endogenous κ light chain immunoglobulin locus, the method comprising:(a) introducing a DNA fragment into a mouse embryonic stem cell, said DNA fragment comprising a nucleotide sequence that includes (i) one or more human Vλ gene segments, (ii) one or more human Jλ gene segments, wherein (i) and (ii) are operably linked to an endogenous mouse Cκ gene; (b) obtaining the mouse embryonic stem cell generated in (a); and (c) creating a mouse using the mouse embryonic stem cell of (b).
Claim 27 is drawn to making a genetically modified mouse, comprising the step of:(a) engineering an endogenous κ light chain immunoglobulin locus in the germline genome of the mouse to include:(i) one or more human Vλ gene segments, (ii) one or more human Jλ gene segments, wherein the one or more human Vλ gene segments and the one or more human Jλ gene segments are operably linked to an endogenous mouse Cκ gene; thereby making said genetically modified mouse.
Claim 21 never results in a mouse that is genetically modified. The only mouse disclosed by applicants is one whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain (Examples). The specification lacks written description for introducing DNA into a mouse ES cell and obtaining any non-genetically modified mouse as broadly encompassed by step c). The specification lacks written description for introducing DNA into a mouse ES cell and obtaining any genetically modified mouse as broadly encompassed by step c) other than the one above.
Claims 21 requires the mouse genome has a modified endogenous κ light chain Ig locus never requires the DNA is incorporated into an endogenous κ light chain Ig in the preamble, but there is nothing in the claim, i.e. the ES cell obtained in step a) or the mouse obtained in step c), that indicates the DNA was incorporated into the genome of the ES cell, the germline genome of the mouse, or the endogenous Ig κ light chain gene.
Claims 27 requires engineering an endogenous κ light chain Ig locus in the germline genome of a mouse but never requires exogenous DNA is incorporated into an endogenous κ light chain Ig. No exogenous DNA is introduced in claim 27. The only way described by applicants and the art at the time of filing to make the genetically modified mouse is by introducing exogenous DNA into an isolated mouse ES cell as required in step a) of claim 21. The phrase “to obtain” in claim 27 is an intended use and does not clearly set forth a function of the “engineering” in line 2. There is no clear positive result of the “engineering” in claim 27 that indicates germline genome of the mouse contains a modified endogenous Ig κ light chain gene.
Claims 21 and 27 are missing the essential steps and reagents for making the genetically modified mouse, i.e. introducing DNA comprising human immunoglobulin Vλ and hJλ gene segments (Fig. 3) into isolated mouse ES cells, transplanting the ES cells into a recipient mouse embryo (pg 53, Example 5), and obtaining a genetically modified mouse from the mouse embryo. The specification and the art do not correlate these specific steps to introducing DNA comprising human Vλ and Jλ gene segments operably linked to a mouse Cκ gene as required in claim 21 or to “creating a mouse using the mouse embryonic stem cells of b)” as broadly encompassed by claim 21. The specification and the art do not correlate these specific steps to any “engineering” of a mouse Ig κ light chain “to include” Vλ and Jλ gene segments operably linked to a mouse Cκ gene as broadly encompassed by claim 27.
The term locus in claims 21 and 27 lacks written description. The term “locus” is singular, and “loci” is plural (Wikipedia definition of “locus”, 2023; National Human Genome Res. Institute definition of “locus”, 2023). A locus (singular) is a position in space or an address on a chromosome. A locus may also be considered a single address on a chromosome. It is unclear how a single position in space or a single address on a chromosome further limits the structure of the nucleic acid sequence within the genome after making the hybrid Ig gene. Next, the term "locus" is singular and refers to a single nucleotide on a chromosome or gene, but the genetic modification claimed occurs over a plurality of nucleotides that change the addresses of other nucleotides within the gene. Ergo, the reference point of the "address" is unclear once the DNA encoding the human Ig gene segments has been introduced into the endogenous Ig gene, especially when there are multiple V and J gene segments are inserted into the endogenous gene. Overall, use of the "locus" is grammatically inappropriate, confusing, and fails to capture the structure of the chimeric Ig gene.
The specification lacks written description for “unrearranged” gene segments in claim 23, 29. The metes and bounds of an “unrearranged” Ig gene segment in claim 23 or 29 cannot be determined. It is unclear whether an “unrearranged” Ig Vλ or Jλ is limited to Ig Vλ or Jλ gene segments that remain in the same genomic order and without genomic modification or whether the phrase encompasses any Ig Vλ or Jλ gene segments that maintain their recombination signal sequences (RSSs) before recombination (pg 7, para 58 of 20210051929) in any order. It is unclear whether the gene segments must have their RSSs or if they are optional (as long as they are in the same “unrearranged” order). Accordingly, the concept lacks written description.
Enablement
Claims 21-32 are 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 making a genetically modified mouse whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain, does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The specification does not enable making any genetically modified mouse as broadly encompassed by claims 21 and 27 other than a genetically modified mouse whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain.
Claims 21 and 27 are recited above.
Claim 21 never results in a mouse that is genetically modified. The only mouse disclosed by applicants is one whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain (Examples). The specification does not enable introducing DNA into a mouse ES cell and obtaining any non-genetically modified mouse as broadly encompassed by step c). The specification does not enable introducing DNA into a mouse ES cell and obtaining any genetically modified mouse as broadly encompassed by step c) other than the one above.
Claims 21 requires the mouse genome has a modified endogenous κ light chain Ig locus never requires the DNA is incorporated into an endogenous κ light chain Ig in the preamble, but there is nothing in the claim, i.e. the ES cell obtained in step a) or the mouse obtained in step c), that indicates the DNA was incorporated into the genome of the ES cell, the germline genome of the mouse, or the endogenous Ig κ light chain gene.
Claims 27 requires engineering an endogenous κ light chain Ig locus in the germline genome of a mouse but never requires exogenous DNA is incorporated into an endogenous κ light chain Ig. No exogenous DNA is introduced in claim 27. The only way described by applicants and the art at the time of filing to make the genetically modified mouse is by introducing exogenous DNA into an isolated mouse ES cell as required in step a) of claim 21. The phrase “to obtain” in claim 27 is an intended use and does not clearly set forth a function of the “engineering” in line 2. There is no clear positive result of the “engineering” in claim 27 that indicates germline genome of the mouse contains a modified endogenous Ig κ light chain gene.
Claims 21 and 27 are missing the essential steps and reagents for making the genetically modified mouse, i.e. introducing DNA comprising human immunoglobulin Vλ and hJλ gene segments (Fig. 3) into isolated mouse ES cells, transplanting the ES cells into a recipient mouse embryo (pg 53, Example 5), and obtaining a genetically modified mouse from the mouse embryo. The specification and the art do not correlate these specific steps to introducing DNA comprising human Vλ and Jλ gene segments operably linked to a mouse Cκ gene as required in claim 21 or to “creating a mouse using the mouse embryonic stem cells of b)” as broadly encompassed by claim 21. The specification and the art do not correlate these specific steps to any “engineering” of a mouse Ig κ light chain “to include” Vλ and Jλ gene segments operably linked to a mouse Cκ gene as broadly encompassed by claim 27.
The term locus in claims 21 and 27 is not enabled. The term “locus” is singular, and “loci” is plural (Wikipedia definition of “locus”, 2023; National Human Genome Res. Institute definition of “locus”, 2023). A locus (singular) is a position in space or an address on a chromosome. A locus may also be considered a single address on a chromosome. It is unclear how a single position in space or a single address on a chromosome further limits the structure of the nucleic acid sequence within the genome after making the hybrid Ig gene. Next, the term "locus" is singular and refers to a single nucleotide on a chromosome or gene, but the genetic modification claimed occurs over a plurality of nucleotides that change the addresses of other nucleotides within the gene. Ergo, the reference point of the "address" is unclear once the DNA encoding the human Ig gene segments has been introduced into the endogenous Ig gene, especially when there are multiple V and J gene segments are inserted into the endogenous gene. Overall, use of the "locus" is grammatically inappropriate, confusing, and fails to capture the structure of the chimeric Ig gene.
The specification does not enable “unrearranged” gene segments in claim 23, 29. The metes and bounds of an “unrearranged” Ig gene segment in claim 23 or 29 cannot be determined. It is unclear whether an “unrearranged” Ig Vλ or Jλ is limited to Ig Vλ or Jλ gene segments that remain in the same genomic order and without genomic modification or whether the phrase encompasses any Ig Vλ or Jλ gene segments that maintain their recombination signal sequences (RSSs) before recombination (pg 7, para 58 of 20210051929) in any order. It is unclear whether the gene segments must have their RSSs or if they are optional (as long as they are in the same “unrearranged” order). Accordingly, the concept is not enabled.
Indefiniteness
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 21-27 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.
Claims 21 and 27 never result in a mouse that is genetically modified. The only mouse disclosed by applicants is one whose genome comprises: (i) a first light chain allele comprising human variable lambda (Vλ) and joining lambda (Jλ) gene segments operably linked to an endogenous mouse constant kappa (Cκ) gene, wherein the mouse expresses an immunoglobulin light chain that comprises a human Vλ domain sequence fused with a mouse Cκ domain; and (ii) a second light chain allele comprising human variable kappa (Vκ) and joining kappa (Jκ) gene segments operably linked to an endogenous mouse Cκ gene such that the mouse expresses an immunoglobulin light chain that comprises a human Vκ domain sequence fused with a mouse Cκ domain (Examples). This is considered essential to the invention but is missing from the claim.
Claims 21 and 27 are missing essential reagents and steps for making the genetically modified mouse, i.e. introducing DNA comprising human immunoglobulin Vλ and hJλ gene segments (Fig. 3) into isolated mouse ES cells, transplanting the ES cells into a recipient mouse embryo (pg 53, Example 5), and obtaining a genetically modified mouse from the mouse embryo. The specification and the art do not correlate these specific steps to introducing DNA comprising human Vλ and Jλ gene segments operably linked to a mouse Cκ gene as required in claim 21 or to “creating a mouse using the mouse embryonic stem cells of b)” as broadly encompassed by claim 21. The absence of these reagents and steps make the claims indefinite.
The term locus in claims 21 and 27 makes the claims indefinite. The term “locus” is singular, and “loci” is plural (Wikipedia definition of “locus”, 2023; National Human Genome Res. Institute definition of “locus”, 2023). A locus (singular) is a position in space or an address on a chromosome. A locus may also be considered a single address on a chromosome. It is unclear how a single position in space or a single address on a chromosome further limits the structure of the nucleic acid sequence within the genome after making the hybrid Ig gene. Next, the term "locus" is singular and refers to a single nucleotide on a chromosome or gene, but the genetic modification claimed occurs over a plurality of nucleotides that change the addresses of other nucleotides within the gene. Ergo, the reference point of the "address" is unclear once the DNA encoding the human Ig gene segments has been introduced into the endogenous Ig gene, especially when there are multiple V and J gene segments are inserted into the endogenous gene. Overall, use of the "locus" is grammatically inappropriate, confusing, and fails to capture the structure of the chimeric Ig gene.
The metes and bounds of “unrearranged” gene segments in claim 23, 29 cannot be determined. The metes and bounds of an “unrearranged” Ig gene segment in claim 23 or 29 cannot be determined. It is unclear whether an “unrearranged” Ig Vλ or Jλ is limited to Ig Vλ or Jλ gene segments that remain in the same genomic order and without genomic modification or whether the phrase encompasses any Ig Vλ or Jλ gene segments that maintain their recombination signal sequences (RSSs) before recombination (pg 7, para 58 of 20210051929) in any order. It is unclear whether the gene segments must have their RSSs or if they are optional (as long as they are in the same “unrearranged” order). Accordingly, the concept makes the claims indefinite.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 10266803. Although the claims at issue are not identical, they are not patentably distinct from each other because they both require a mouse with human V lambda and human J lambda operably linked to an endogenous mouse C kappa gene.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9844212. Although the claims at issue are not identical, they are not patentably distinct from each other because they both require a mouse with human V lambda and human J lambda operably linked to an endogenous mouse C kappa gene and a human V kappa and human J kappa operably linked to an endogenous mouse C kappa gene.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of U.S. Patent No. 9394373. Although the claims at issue are not identical, they are not patentably distinct from each other because they both require a mouse with human V lambda and human J lambda operably linked to an endogenous mouse C kappa gene and a human V kappa and human J kappa operably linked to an endogenous mouse C kappa gene.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9850462, 9540452, 9226484, 9206263, 9006511, 9012717. Although the claims at issue are not identical, they are not patentably distinct from each other because they both require a mouse with human V lambda and human J lambda operably linked to an endogenous mouse C kappa gene and a human V kappa. While they do not require the mouse has human J kappa operably linked to an endogenous mouse C kappa gene, they are intermediates in an intermediate-final product relationship and have been acknowledged by applicants as being grouped together in application 15/398410 and 14/561867.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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