DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 50, 56, 58 have been canceled. Claims 1-49, 51-55, 57 are pending.
Election/Restrictions
Applicant’s election of Group IV, claims 49-52, 54-58, in the reply filed on 12-8-25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-48, 53 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12-8-25.
Claims 49, 51, 52, 54, 55, 57 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.
Claim Rejections - 35 USC § 112
Claims 49, 51, 52, 54, 55, 57 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.
Claim 49 is drawn to a genetically modified non-human animal, wherein the genome of the animal comprises: at least one modified allele comprising an unrearranged un-rearranged immunoglobulin heavy chain variable domain (VH) coding segment, at least one un-rearranged immunoglobulin heavy chain D domain coding segment, and one un-rearranged immunoglobulin heavy chain J domain coding segment that is operably linked to a functional non-human immunoglobulin heavy chain constant gene sequence, wherein the CH1 domain coding sequence from a lgG3 constant region is deleted, thereby enabling rearrangement of the V, D and J coding segments and expression of antibodies that consist of IgG3 heavy chain only antibodies by B cells in the genetically modified non-human animal.
The claim encompasses any species of non-human animal including invertebrate, insect, fish, amphibian, reptile, bird, or non-human mammal. The “modified allele” may be exogenous or endogenous. The metes and bounds of when a Ig VH, DH, or JH gene segment are “unrearranged” cannot be determined. The “functional non-human” Ig CH gene may be endogenous or exogenous to the “non-human animal” or to the Ig VH, DH, and JH gene segments.
Janssens (PNAS, 2006, 103:15130-15135) and Zou (J. Exp. Med., 2007, 204:3271-3283) taught genetically modified mice that lack a functional CH1 sequence, e.g., in an immunoglobulin G (IgG) gene, subsequently expressed single domain antigen binding proteins. (para 104).
MacDonald (20110145937) taught genetically modified mice whose genomes comprises an IgG3 heavy chain gene that lacks a functional CH1 (para 68, 78, 88, 89, 96, 127; claim 17) and a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (claim 4, 10, 12-17). The mice make “camelized” antibodies that are only heavy chains (para 3, 11, 56, 97, 119, et al). This is equivalent to claim 49. The mice have a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (claim 4, 10, 12-17) as required in claim 51.
Grosveld (20140356908) taught genetically modified mice whose genomes comprises an Ig heavy chain IgG1 gene that lacked a functional CH1 and a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (Fig. 1, claim 1).
MacDonald (20150289489) taught genetically modified mice whose genomes comprises an Ig heavy chain gene in which the heavy chain constant region lacking a functional CH1 (claim 40) and a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (para 14).
The specification is limited to targeting an endogenous Ig heavy chain gene of a mouse with a vector that replaces all endogenous VH, JH and DH gene segments with a plurality of human VH, JH, and DH gene segments. The plurality of human VH, JH, and DH gene segments are operably linked to an endogenous CH gene in which an IgG3 gene has an inactivated CH1 domain. IgM and IgD exons were deleted along with IgM-, IgG3-, and IgA- switch regions (pg 5, para 30 or 31). Mice obtained from the genetic modification are capable of producing heavy chain only antibodies comprising a human VH domain and an IgG3 constant domain (Fig. 1, pg 3, par 12).
The specification fails to correlate genetically modified mice to any other non-human animal. In particular, the claims encompass llamas which naturally make heavy chain antibodies, but applicants fail to teach how to modify llamas to make the genome claimed.
The specification fails to teach ANY modified Ig heavy chain gene as broadly encompassed by claim 49 other than a mouse whose genome comprises a deletion of an endogenous sequence encoding a CH1 domain of an IgG3 constant gene, wherein the mouse is capable of expressing a heavy chain only IgG3 antibody. The specification fails to correlate the genetically modified mouse to any other invertebrate, insect, fish, amphibian, reptile, bird, or non-human mammal as broadly encompassed by claim 49. The specification does not correlate this limited embodiment to any “modified allele” or enabling any “rearrangement of the V, D and J coding segments and expression of antibodies that consist of IgG3 heavy chain only antibodies by B cells in the genetically modified non-human animal” as broadly encompassed by claim 49. The specification fails to correlate deleting the switch regions of the endogenous Ig heavy chain intact as well as the endogenous IgM and IgA genes to leaving them intact as broadly encompassed by claim 49. The specification fails to teach any “introduced” Ig VH, DH, or JH gene segments as broadly encompassed by claim 51 other than human Ig VH, DH, or JH gene segments. The specification fails to correlate the mice to any rat, beaver, squirrel, groundhog, muskrat, hamster, capybara, chinchilla, porcupine, gerbil, or any rodent as required in claim 54 other than mouse.
The specification lacks written description for an Ig heavy chain “locus” in claim 57 are unclear. First, “locus” is singular, and “loci” is plural (Wikipedia definition of “locus”, 2023; National Human Genome Res. Institute definition of “locus”, 2023). Second, locus (singular) is a position in space or an address on a chromosome. Third, the specification does not define an Ig heavy chain “locus” (singular) as and an Ig heavy chain gene (which must have a plurality of nucleotides) or as a plurality of nucleotides encoding an Ig heavy chain constant domain. Fourth, the specification is limited to replacing a plurality of endogenous nucleotides (at a plurality of contiguous “loci” (plural)) with a plurality of exogenous nucleotides. The specification does not teach the exogenous nucleotides are present at a single locus, position, or address on the chromosome as claimed. Replacing pluralities of nucleotides is not replacing a nucleotide at a single locus as claimed. Fifth, the concept claimed does not accurately set forth the genetic modification because the addresses and positions of the nucleotides within the endogenous Ig heavy chain gene have changed because of differences in the length caused by the genetic modification. Accordingly, use of an Ig heavy chain “locus” lacks written description.
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 49, 51, 52, 54, 55, 57 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The metes and bounds of an “unrearranged” Ig gene segment in claim 49 cannot be determined. It is unclear whether an “immunoglobulin heavy chain variable domain (VH) coding segment” is limited to Ig VH gene segments that remain in the same genomic order and without genomic modification or whether the phrase encompasses any Ig heavy chain 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, those of skill would not be able to determine when they were infringing on the claim.
The metes and bounds of an Ig heavy chain “locus” in claim 57 are unclear. First, “locus” is singular, and “loci” is plural (Wikipedia definition of “locus”, 2023; National Human Genome Res. Institute definition of “locus”, 2023). Second, locus (singular) is a position in space or an address on a chromosome. Third, the specification does not define an Ig heavy chain “locus” (singular) as and an Ig heavy chain gene (which must have a plurality of nucleotides) or as a plurality of nucleotides encoding an Ig heavy chain constant domain. Fourth, the specification is limited to replacing a plurality of endogenous nucleotides (at a plurality of contiguous “loci” (plural)) with a plurality of exogenous nucleotides. The specification does not teach the exogenous nucleotides are present at a single locus, position, or address on the chromosome as claimed. Replacing pluralities of nucleotides is not replacing a nucleotide at a single locus as claimed. Fifth, the concept claimed does not accurately set forth the genetic modification because the addresses and positions of the nucleotides within the endogenous Ig heavy chain gene have changed because of differences in the length caused by the genetic modification. Accordingly, those of skill would not be able to determine when they were infringing on the claim.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
A) Claims 49, 51, 52, 54, 55 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by MacDonald (20110145937).
MacDonald taught genetically modified mice whose genomes comprises an IgG3 heavy chain gene that lacks a functional CH1 (para 68, 78, 88, 89, 96, 127; claim 17) and a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (claim 4, 10, 12-17). The mice make “camelized” antibodies that are only heavy chains (para 3, 11, 56, 97, 119, et al). This is equivalent to claim 49.
The mice have a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (claim 4, 10, 12-17) as required in claim 51.
The mice are heterozygous (para 12, 139, 155, 158, 161, 167) as required in claim 52.
MacDonald made a mouse which is a rodent as required in claim 54.
MacDonald made a mouse as required in claim 55.
B) Claims 49, 51, 52, 54, 55, 57 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by MacDonald (20150289489) taught genetically modified mice whose genomes comprises an Ig heavy chain gene in which the heavy chain constant region lacking a functional CH1 (claim 40) and a replacement of one or more, or all, endogenous immunoglobulin heavy chain variable region gene segments with one or more unrearranged human immunoglobulin VH, JH, and DH gene segments (para 14).
"FIG. 1A illustrates targeting a mouse IgG1 gene, IgG2b and IgG2a genes (not to scale) to make a genetically modified mouse immunoglobulin heavy chain locus that expresses an IgG1 lacking a CH1 domain; human immunoglobulin heavy chain V, D and J segments, represented by empty triangles, are inserted to a mouse constant locus wherein the IgG1 CH1 exon* and IgG2a/2b* are deleted, ovals represent enhancers.” [0041].
"FIG. 4A illustrates targeting a mouse heavy chain sequence (not to scale) to make a genetically modified locus that contains human heavy chain variable gene segments (empty triangles) and lacks a functional lgG1 CH1 domain as well as lacks lgG2a and lgG2b loci (in some embodiments referred to as 1673)." [0046].
The heavy chain lacks a C.sub.H1 domain, including single domain antigen binding proteins, such as but not limited to V.sub.H and V.sub.L single domain binding proteins. The genetic modification may include a lack of a functional immunoglobulin heavy chain domain (a C.sub.H1 domain), e.g., an IgG1 C.sub.H1 domain, and in some embodiments a further modification comprising a deletion of a hinge region in the immunoglobulin heavy chain that lacks the functional C.sub.H1 domain, wherein the non-human animal expresses a functional IgM. Other modifications include rendering isotypes other than IgG1 and IgM to be nonfunctional, e.g., making deletions in genes, or deletions of genes, or inactivating mutations in genes, for IgD, IgG3, IgG2a, IgG2c, IgG2b, IgA, and IgE, such as deletions or inactivating mutations of CH1 domains or hinge regions of IgD, IgG3, IgG2a, IgG2c, IgG2b, IgA, and IgE. [0112]
"The term "heavy chain only antibody,' 'heavy chain only antigen binding protein,' 'single domain antigen binding protein,' "single domain binding protein' or the like refers to a monomeric or homodimeric immunoglobulin molecule comprising an immunoglobulin-like chain comprising a variable domain operably linked to a heavy chain constant region, that is unable to associate with a light chain because the heavy chain constant region typically lacks a functional CH1 domain." [0082].
"The phrase 'gene segment,' or 'segment' includes reference to a V (light or heavy) or D or J (light or heavy) immunoglobulin gene segment, which includes unrearranged sequences at immunoglobulin loci (in e.g., humans and mice) that can participate in a rearrangement (mediated by, e.g., endogenous recombinases) to form a rearranged V/D/J (heavy) sequence.” (para 74).
Therefore, MacDonald taught a genetically modified mouse whose genome comprises unrearranged Ig VH, JH, and DH gene segments operably linked to an endogenous IgG3 gene in which the CH1 domain has been inactivated, wherein the VH, JH, and DH gene segments are capable of rearranging in B-cells of the mouse such that IgG3 heavy chain only antibodies are expressed as required in claim 49.
Claim 51 has been included because does not further limit claim 49 because claim 49 already requires the VH, JH, and DH gene segments are capable of rearranging in B-cells of the mouse such that IgG3 heavy chain only antibodies.
Claim 52 has been included because MacDonald taught the mice are heterozygous (para 186).
MacDonald made a mouse which is a rodent as required in claim 54.
MacDonald made a mouse as required in claim 55.
MacDonald deleted IgM and IgD constant regions and IgM, IgD, and IgG3 switch regions as required in claim 57 (para 48, 49, 147).
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Conclusion
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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