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, 51, 54-58 have been canceled. Claims 1-49, 52, 53 remain pending.
Applicant's arguments filed 7-28-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
There are discrepancies for support cited by applicants on pg 9 and throughout the response filed 7-28-26. For example, the phrase “Production [of] IgM and IgD antibodies is ablated due to deletion of these constant regions” is in paragraph 102 of the original disclosure, not paragraph 97. The discrepancy arises because para 102 of the original disclosure is para 97 of the Published Application 2023/0062964.
When referencing the specification, please use page and paragraph number (and line number as necessary) of the original specification. Do not simply use paragraph numbers. Do not refer to paragraphs of the US Patent Application Publication because there are frequent discrepancies.
Election/Restrictions
Applicants elected Group IV, claims 49-52, 54-58, in the reply filed on 12-8-25.
Claims 1-48, 53 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 49, 52 remain under consideration.
Claim Rejections - 35 USC § 112
Written Description
Claims 49, 52 remain 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 mouse whose genome comprises a plurality of unrearranged immunoglobulin (Ig) heavy chain variable (VH) gene segments, a plurality of unrearranged Ig heavy chain joining (JH) gene segments, and a plurality of unrearranged Ig heavy chain diversity (DH) gene segments operably linked to an endogenous Ig heavy chain constant region comprising an endogenous IgG3 gene that comprises a deleted nucleic acid sequence encoding its CH1 domain, a deleted IgM gene, a deleted IgD gene and lacking IgM, IgD, and IgG3 switch regions, wherein B-cells of said mouse are capable of expressing IgG3 heavy chain-only antibodies (HCAbs) and are incapable of expressing IgGi, IgG2, IgG4, IgA, IgE,IgM, or IgD antibodies.
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 lacks written description for any species of “unrearranged” Ig VH, DH, or JH gene segments as required in claim 49 other than human. The “unrearranged” Ig VH, DH, or JH gene segments can be endogenous or exogenous. The exogenous gene segments encompass those from fish, amphibians, reptiles, birds, or non-mouse mammals, e.g. elephant, gazelle, deer, antelope, camel, elk, whale, dolphin, tiger, leopard, cheetah, dingo, wolf, beaver, mole, vole, otter, et al. 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 specification does not correlate the “unrearranged” human gene segments to an endogenous VH, JH, and DH gene segments. Therefore, the concept lacks written description.
The specification lacks written description for any “unrearranged” Ig VH, DH, or JH gene segments as required in claim 49. The metes and bounds of when Ig VH, DH, or JH gene segments are “unrearranged” cannot be determined. It is unclear whether they are 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, the concept lacks written description.
The specification lacks written description for any “endogenous Ig heavy chain constant region” as broadly encompassed by claim 49 other than an endogenous CH gene comprising: i) an IgG3 gene with an inactivated CH1 domain, ii) inactivated IgM and IgD genes, and iii) inactivated IgM-, IgG3-, and IgA- switch regions. The structure of the “endogenous Ig heavy chain constant region…” cannot be determined because the “deleted” language is vague. It is unclear if the coding sequence has any deletion (of one or more nucleotides), whether the entire coding sequence has been deleted, or whether the coding sequence as simply been inactivated. The specification is limited to human VH, JH, and DH gene segments 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 can produce “heavy chain only” antibodies comprising a human VH domain and an IgG3 constant domain (Fig. 1, pg 3, par 12) but cannot produce IgG1, IgG2, IgG4, IgA, IgE, IgM, or IgD. The constant region should be limited to an endogenous CH gene comprising: i) an IgG3 gene with an inactivated CH1 domain, ii) inactivated IgM and IgD genes, and iii) inactivated IgM-, IgG3-, and IgA- switch regions.
Response to arguments
Applicants point to paragraphs 80, 63, 97, 62, 32, Fig. 2A. Applicants’ argument is not persuasive because the deletions and inactivations in claim 49 are vague.
Indefiniteness
Claims 49, 52 remain 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.
Response to arguments
Applicants “unrearranged” gene segments had a well-known definition as retaining their RSSs as supported by para 53, 64; paragraph 24 of MacDonald (20110145937); and paragraph 14 of MacDonald (20150289489). Applicants’ argument is not persuasive. Para 53 describes VDJ recombination but does not mention or define “unrearranged” gene segments. Para 63 describes “Model I” design of gRNAs but does not mention or define “unrearranged” gene segments. Para 24 of MacDonald (20110145937) uses the phrase “unrearranged” gene segments but does not define when gene segments are “unrearranged”. Para 12 of MacDonald (20150289489) uses the phrase “unrearranged” gene segments but does not define when gene segments are “unrearranged”.
Claim Rejections - 35 USC § 102
The rejection of claims 49, 52 under 35 U.S.C. 102(a)(2) as being anticipated by MacDonald (20110145937) has been withdrawn because ‘937 did not teach inactivating an endogenous IgM gene as required in claim 49.
The rejection of claims 49, 52 under 35 U.S.C. 102(a)(2) as being anticipated by MacDonald (20150289489) has been withdrawn because ‘937 did not teach inactivating an endogenous IgM gene as required in claim 49.
The art at the time of filing did not teach or suggest a genetically modified mouse whose genome comprises a plurality of unrearranged immunoglobulin (Ig) heavy chain variable (VH) gene segments, a plurality of unrearranged Ig heavy chain joining (JH) gene segments, and a plurality of unrearranged Ig heavy chain diversity (DH) gene segments operably linked to an endogenous Ig heavy chain constant region comprising an endogenous IgG3 gene that comprises a deleted nucleic acid sequence encoding its CH1 domain, a deleted IgM gene, a deleted IgD gene and lacking IgM, IgD, and IgG3 switch regions, wherein B-cells of said mouse are capable of expressing IgG3 heavy chain-only antibodies (HCAbs) and are incapable of expressing IgGi, IgG2, IgG4, IgA, IgE,IgM, or IgD antibodies as required in claim 49.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
