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 .
Election/Restrictions
1. Applicant’s election of the invention of Group I (drawn to a genetically engineered mammalian cell) in the reply filed on 05/08/2026 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 20-23 have been cancelled. Claims 1, 5-8, and 10 have been amended. Claims 24-35 are new.
Claims 11-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claims 1-10 and 24-35 are under examination.
Claim Objections
2. Consistent with the specification, it is suggested that claim 1 be amended to recite:
“A genetically engineered recombinant genome of non-human mammalian cell,
wherein endogenous immunoglobulin variable region genes in the genome are partially or entirely replaced by human immunoglobulin variable region genes,
wherein a part or all of the pseudogenes and/or open reading frames of the human immunoglobulin variable region genes are knocked out,
wherein the human variable region genes are heavy chain variable region genes and/or kappa light chain variable region genes and/or lambda light chain variable region genes,
wherein the number of the pseudogenes and/or open reading frame genes of the human immunoglobulin variable region genes knocked out is set such that the length of the heavy chain variable region gene inserted into the genome of the non-human mammalian cell is 10%-50% of the total length of the human immunoglobulin heavy chain variable region gene before the knockout of the pseudogenes and/or open reading frame genes; the length of the lambda light chain variable region gene inserted into the genome of the non- human mammalian cell is 10%-50% of the total length of the lambda light chain variable region gene before the knockout of the pseudogenes and/or open reading frame genes; the length of the human immunoglobulin kappa light chain variable region gene inserted into the genome of the non-human mammalian cell is 35%-65% of the total length of the human immunoglobulin kappa light chain variable region gene before the knockout of the pseudogenes and/or open reading frame genes,
wherein (1) the complete size of the inserted human heavy chain V region is 940130 bp, according to positions between 105939715 and 106879844 of chromosome 14 of ENSEMBL GRCh38.p13; (2) the complete size of the inserted human kappa light chain proximal V region is 471464 bp, according to positions between 88861968 and 89333431 of chromosome 2 of ENSEMBL GRCh38.p13; and (3) the complete size of the inserted human lambda light chain V region is 858318 bp, according to positions between 22023114 and 22881431 of chromosome 22 of ENSEMBL GRCh38.p13.
3. Applicant is advised that should claim 27 be found allowable, claim 28 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(d)
4. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
5. Claims 24-28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Independent claim requires the human heavy chain locus to have a complete size of 940130 bp corresponding to the positions between 105939715 and 106879844 of chromosome 14, i.e., all VH gene segments identified as H3-H67 in the table disclosed in claim 24 (it is noted that this recitation in claim 1 excludes H1).
However, dependent claim 24 recites any two or more selected from H1-H67; claim 25 recites 10-41; claim 26 recites 15-41; and claims 27 and 28 recite 25-41. These recitations include H1, which is excluded from the parent claim 1; and human heavy chain loci of less than 940130 bp (not including all H3-H67), as required by the parent claim 1. Thus, claims 24-28 fail to further limit the subject matter of the parent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
6. 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 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.
7. Claims are rejected under 35 U.S.C. 103 as being unpatentable over Murphy et al. (PNAS, 2014, 111: 5153-5158), in view of Karan-Djurasevic et al. (Lymphocyte
Updates - Cancer, Autoimmunity and Infection, 2017, Chapter 3, p. 49-78), as evidenced by both Mendez et al. (Nature Genetics, 1997, 15: 146-156) and Lefranc et al. (Exp. Clin. Immunogenet., 2001, 18: 161-174).
Claim 1 recites heavy chain; kappa light chain; lambda light chain. Although claim 1 does not specify whether the chains are recited in the alternative or not, consistent with the specification (see p. 10, second paragraph) and the dependent claim 2, claim 1 is reasonably interpreted as reciting heavy chain and/or kappa light chain and/or lambda light chain.
Murphy et al. teach a mouse embryonic stem cell genetically modified by completely replacing the mouse Ig heavy and kappa light variable region germline gene segments with the human counterparts and operably linking the human counterparts to the respective mouse constant regions. The human Ig heavy variable region comprises the germline VH6-1 to VH3-74 and all DH/JH gene segments; the human Ig kappa light chain comprises the germline VK4-1 to VK2-40 and JK gene segments. The embryonic stem cell is used to obtain the transgenic mouse VelocImmune III (V3) comprising the genetic modifications in its B-cells (claims 1-3, 8-10, and 35) (see Abstract; p. 5153, column 2; p. 5154; paragraph bridging p. 5155 and 5156; p. 5157, column 1). Since Murphy et al. teach completely deleting the mouse Ig heavy and kappa light variable region germline gene segments, one skill in the art would have reasonably concluded that the deleted mouse Ig heavy chain variable region is located between positions 113428530 and 116027502 on mouse chromosome 12 ; and the deleted endogenous Ig kappa light chain variable region is located between positions 67536984 to 70723924 on mouse chromosome 6 (claim 8).
As evidenced by Mendez et al., the germline gene segments VH6-1 to VH3-74 comprise the VH gene segments recited in claims 24-28 (see Mendez et al., p. 147, Fig. 1). As evidenced by claim 24, VH6-1 to VH3-74 are between positions 105944896 and 106822782 on chromosome 14 (claims 1 and 4). Since Murphy et al. teach that human Ig heavy gene segments include all DH/JH gene segments, it is reasonable to conclude that the human Ig heavy gene segments comprises the nucleotide positions 105944896 and 106879844 from human chromosome 14 (claim 5).
With respect to claim 29, the recitation “comprise two or more from the V region genes K1-K30 and L1-L49” does not require the genes to comprise both VK and VL genes. Thus, the cell comprising only the VK4-1 to VK2-40 genes taught by Murphy et al. reads on the claim. As evidenced by Mendez et al. and Lefranc et al., the germline gene segments VK4-1 to VK2-40 comprise the VK gene segments recited in claim 29 (see Mendez et al., p. 147, Fig. 1; see Lefranc et al., p. 171, Table 3). As evidenced by claim 29, VK4-1 to VK2-40 are between positions 88861968 and 89333431 on chromosome 2 (claims 1 and 4). Since Murphy et al. teach that human Ig kappa gene segments all JK gene segments, one of skill in the art would have reasonably concluded that the human Ig heavy gene segments comprises the nucleotide positions 88861968 and 90235398 from human chromosome 2 (claim 6).
With respect to claim 7, since Murphy et al. teach replacing the mouse Ig heavy and kappa light variable region germline gene segments with the human counterparts, one of skill in the art would have reasonably concluded that the human counterparts are inserted at a location between 3kb upstream to 3kb downstream from the deleted mouse Ig heavy and kappa light variable region germline gene segments.
Murphy et al. do not teach deleting the pseudogenes (claim 1). Karan-Djurasevic et al. teach that, given to the number of gene segments that can recombine at Ig loci and the random pairing of heavy and light chains, B-cells exhibit combinatorial diversity and could produce a vast number of different antibodies. Karan-Djurasevic et al. teach that the mechanisms responsible for the variability of immunoglobulin rearrangements can render the B-cells nonproductive due to recombination pseudogenes, leading to B-cells wastage. Karan-Djurasevic et al. teach that B cells which fail to generate productive rearrangements and produce functional antibodies undergo apoptotic cell death (see p. 53 through p. 54, first paragraph; p. 56, first paragraph). Based on these teachings, one of skill in the art would have reasonably concluded that removing the pseudogenes would increase the numbers of B-cells generating productive rearrangements. One of skill in the art would have found obvious to modify Murphy et al. by removing the pseudogenes from the human Ig loci, with the reasonable expectation that doing so would enhance the yield of productive rearrangement, and thus, the yield of functional antibodies.
With respect to the lengths recited in claims 1 and 30-33, there is no evidence that the recited length ranges are associated with unexpected results. One of skill in the art would have reasonable concluded that the number of pseudogenes is a result-effective variable with respect to the efficiency of productive rearrangements. One of skill in the art would have found obvious to use routine experimentation and vary the number of pseudogenes to be removed, with the reasonable expectation that doing so would identify the conditions for optimal production of functional antibodies. Routine optimization is not considered inventive and no evidence has been presented that the selection of the claimed ranges was other than routine or that the results should be considered unexpected in any way as compared to the closest prior art (see MPEP 2144.05 II).
With respect to claim 34, Murphy et al. do not specifically teach the claimed insertions sites. However, it is noted that there is no evidence of record indicating that these insertion sites are associated with unexpected properties over Murphy et al. As per MPEP § 716.02, [a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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