DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-27, 31, 32, 34-42, 45, 46, 49-73 have been canceled. Claims 28-30, 33, 43, 44, 47, 48 remain pending.
Applicant's arguments filed 10-3-25 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.
Election/Restrictions
Applicants elected Group II, claims 36-42 (a rodent comprising a nucleic acid encoding a chimeric β2 microglobulin), in the response filed 2-5-24. Group I, claims 27-35, was recombined with Group II in the office action sent 5-2-24.
Claims 43, 44, 47, 48 remain withdrawn.
Claims 28-30, 33 remain under consideration.
Priority
This application is a DIV of 15/439,828 filed 02/22/2017, now PAT 10,869,466; which is a DIV of 13/661,159 filed 10/26/2012, now PAT 9,615,550.
This application is claiming the benefit under 35 U.S.C. 119(e) of prior-filed provisional applications 61/700,908, filing date 09/14/2012, 61/552,582 filing date 10/28/2011 and 61/552,587 filing date 10/28/2011.
The disclosure of the prior-filed application, 61/552,582, filed on 10/28/2011, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, 61/552,582 does not support original claims 31-33 and 39-41, wherein the rodents and mice comprise exon 2 to exon 4 of a human β2 microglobulin gene and exons 2, 3, and 4 of a human β2 microglobulin gene.
Page 5, paragraph [0012] of prior-filed provisional application 61/700,908 provides support for original claims 31-33 and 39-41 at least in paragraph [0012]:
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Thus, the earliest possible priority for original claims 31-33 and 39-41 of the instant application is September 14, 2012. If Applicant believes the earlier applications provide support for this disclosure, Applicant should point out such support by page and line number in the reply to this Action.
Claim Objections
Claim 33 can be written more clearly as ---The genetically modified mouse of claim 28 whose genome comprises exon 1 of an endogenous β2 microglobulin gene operably linked to the nucleic acid sequence comprising exons 2-4 of a human β2 microglobulin gene ---.
Claim Rejections - 35 USC § 112
Written Description
The rejection of claims 28-30, 33 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, has been withdrawn. The rejection regarding a rodent having a replacement “at an endogenous β2 microglobulin locus” as required in claim 28 has been withdrawn in view of the amendment.
Claim Rejections - 35 USC § 103
Claims 28-30, 33 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Pascolo (J. Exp. Med., 1997, pg 2043-2051) in view of Littman (5859312), Karlsson (WO 9941365), Gotoh (7339089), Stacey (Mol. & Cell. Biol., 1994, pg 1009-1016), Gussow (J. Immunol., 1987, Vol. 139, pg 3131-3138), Israel (PNAS, 1987, Vol. 84, pg 2653-2657) and Lonergan (Mol. & Cell. Biol., 1993, Vol. 13, pg 6629-6639).
Pascolo taught a genetically modified mouse whose genome comprises a knockout of an endogenous β2 microglobulin (β2m) gene (including exons 2-4) and a nucleic acid sequence encoding human β2m (including exons 2-4) (pg 2045, “HHH” and “HHC” mice). The sequence encoding human β2m described by Pascolo integrated randomly into the genome of the mouse.
Pascolo did not teach replacing an endogenous β2m coding sequence with an human β2m coding sequence as required in claim 28.
However, replacing an endogenous mouse gene with an equivalent human coding sequence was well known in the art as shown by Littman (claim 1), Karlsson (claim 8), Gotoh (claim 1), and Stacey (“Materials and Methods”; Fig. 1, 2). Gussow taught the structure of the mouse β2m gene including the promoter and each of its exons and introns (Figures). Israel taught the mouse β2m promoter and enhancer (pg 2654, col. 2, last 6 lines), and Lonergan taught a regulatory element within the mouse β2m promoter (title, abstract, Fig. 1, et al.).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to inactivate an endogenous β2m coding sequences in a mouse and express a human β2 coding sequences as described by Pascolo by replacing an endogenous coding sequence with an equivalent human coding sequence as described by Littman, Karlsson, Gotoh, and Stacey. Those of ordinary skill in the art at the time of filing would have been motivated to replace endogenous exons 2-4 of β2m with human exons 2-4 of β2m to humanize the extracellular portion of β2m. This was well-known as a means for studying the interaction of the extracellular portion of a humanized protein with other proteins in a mouse model as evidenced by Littman, Karlsson, and Gotoh.
Claim 29 has been included because Pascolo taught the endogenous β2m gene was knocked out in “HHH” and “HHC” mice (title, abstract, pg 2043, last full paragraph, etc.).
Claim 30 has been included because those of ordinary skill in the art at the time of filing would have been motivated to leave the endogenous β2m promoter and enhancer intact in the mouse to ensure proper regulation of gene expression in the mouse.
Gussow taught exon 1 of the endogenous β2m gene was the promoter; therefore, the combined teachings of Pascolo, Gussow, Israel, and Longergan taught leaving exon1 of the endogenous β2m gene intact as required in claim 33.
Response to arguments
Applicants argue Pascolo did not suggest a mouse whose genome had a sequence encoding an untranslated human β2m exon 4. Applicants’ argument is not persuasive. Applicants’ argument is not persuasive because the claims are not limited to “untranslated” exon 4. Pascolo used human exons 2-4 which is all that is required to meet the limitation claimed.
Applicants argue Gussow taught a sequence encoding human β2m would include exons 2 and 3 but not 4. Applicants’ argument is not persuasive. While exon 4 may not be translated, it is still an exon encoding an untranslated region that provides stability for expression. It was readily apparent to include exon 4 for proper expression of the human portion of the β2m.
Applicants argue the art taught away from replacing exons 2-4 of a mouse β2m gene with exons 2-4 of a human β2m gene (pg 9). Applicants point to para 104 which sets forth the exons in the human gene. Applicants’ argument is not persuasive. The teachings in para 104 are the same as those in Gussow – this was not a new discovery.
Applicants point to Willinger (2011) who taught the 3’ utr was preserved in knockin mice. Willinger is not persuasive because there is nothing teaching away from using exon 4 of a human β2m gene.
Applicants point to Anderson and Carpenter who taught mRNAs encoding cytokines. Applicants’ argument is not persuasive because there is nothing in Anderson and Carpenter teaching away from using exon 4 of a human β2m gene.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Koller (J. Immunol. 1985, pp. 2727-2733) taught the promoter, introns, and exons of the human β2m gene.
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