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 .
Notice of Revival of Abandonment
It is noted that the petition under the unintentional provisions of 37 CFR 1.137(a), filed
12th, September, 2025, to revive the application was GRANTED in the petition decision filed on 17th, October, 2025. Applicant’s submission filed on 12th, September, 2025 has been entered.
Claim Status
Claims 1, 8-10, 12-15, 28-33, 35, and 37-41 are pending.
Claims 13 and 39-41 are withdrawn.
Claims 1, 8-10, 12, 14-15, 28-33, 35 and 37-38 are under examination.
Election/Restrictions
Applicant’s election without traverse of the following invention
Invention
Group I, claims 1, 8-10, 12-15, 28-33, 35 and 37-38, drawn to a transgenic rodent or rodent cell comprising a genome comprising an engineered partly bovine immunoglobulin light chain locus comprising bovine immunoglobulin light chain variable region gene segments, wherein the engineered immunoglobulin locus is capable of expressing immunoglobulin comprising bovine variable domains and wherein the transgenic rodent produces more, or is more likely to produce, immunoglobulin comprising light chain than immunoglobulin comprising K light chain and a cell of B lymphocyte lineage obtained from the transgenic rodent of claim 1, wherein the engineered immunoglobulin locus expresses a chimeric immunoglobulin heavy chain or light chain comprising a bovine variable region and a rodent immunoglobulin constant region,
in the reply filed on 12th, September, 2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 39-41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s election without traverse of the following species
Species
Transgene location
one or more rodent VK gene segment coding sequences and one or more rodent JK gene segment coding sequences have been deleted and replaced by one or more bovine Vλ gene segment coding sequences and one or more Jλ gene segment coding sequences (coding sequences) (claims 14-15)
in the reply filed on 12th, September, 2025 is acknowledged. Claims 1, 8-10, 12, 14-15, 28-33, 35 and 37-38 encompass the elected species.
The requirement is still deemed proper and is therefore made FINAL.
Claim 13 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Rejections - 35 USC § 112(b)
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 1, 8-10, 12, 14-15, 28-33, 35 and 37-38 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.
Claim 1 recites the transgenic rodent “is more likely to produce” immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain which recites a probability or likelihood of a structure occurring and does not recite a specific requirement for that structure. Because claim 1 recites a thing which may be done (i.e. “more production of immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain”) which is not required to be done ( it is “more likely” and therefore is not required), the scope of claim 1 is indefinite. See Application of Collier, 397 F.2d 1003 (C.C.P.A. 1968), which states claims are considered indefinite when “things which may be done are not required to be done". Specifically, it is unclear whether the claimed product may be infringed if the recited limitation does not occur.
By nature of their ultimate dependency on claim 1, claims 8-10, 12, 14-15, 28-33, 35 and 37-38 are also rejected because they do not clarify the issue.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Claim Interpretation
Claim 1 recites “the transgenic rodent produces more” immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain, which encompasses all amounts of increased expression, including very small increases. Furthermore, because expression fluctuates, this encompasses regular variation in expression that results in an increase in immunoglobulin comprising λ light chain.
Due to the 112b issues identified above, for the sake of compact prosecution, the claims identified with 112 issues above are being examined against the prior art and double-patenting as follows:
As discussed above, the recitation of “is more likely to produce” is indefinite. Because more production does not necessarily occur, this is interpreted as an optional limitation.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 8, 12, 28-33, 35 and 37-38 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wabl et al. (US-20170303517-A1; henceforth “Wabl”) as evidenced by Inlay et al. (Nat Immunol. 2002 May;3(5):463-8. Epub 2002 Apr 22.; henceforth “Inlay”).
Regarding claim 1, Wabl discloses a transgenic rodent (mouse) or rodent cell (ES cell clones) comprising a genome comprising an engineered partly bovine (“transgenic mammals that express bovine-based immunoglobulins, including transgenic rodents that express bovine-based immunoglobulins” abstract) immunoglobulin light chain locus comprising bovine immunoglobulin λ light chain variable region gene segments (“an array of 25 bovine lambda variable region gene segments” para. [0135]); Examples 4-6; Figures 2-11; see also claims 1-2).
Regarding claim 1, the transgenic moue disclosed by Wabl comprises rodent (mouse) cells that comprise the engineered partly bovine immunoglobulin light chain locus comprising bovine immunoglobulin λ light chain variable region gene segments (see also claim 3).
Additionally, regarding claim 1, Wabl discloses mouse or rat embryonic stem (ES) cells with eh claimed features (“Mouse embryonic stem (ES) cells derived from C57B1/6NTac mice” para. [0126]; see also para. [0025-0027, 0031, 0056, 0061, 0090, 0094, 0096-0097, 0110-0111, 0113, 0115, 0117, 0119-0120, 0127, 0129-0130, 0133, 0137-0138, 0143-0148, 0151-0152]; claims 23-24).
Regarding claim 1, concerning the limitation that “the engineered immunoglobulin locus is capable of expressing immunoglobulin comprising bovine variable domains,” the mouse disclosed by Wabl comprises the bovine variable domains in its genome and is therefore capable of expressing the domains. Additionally, Wabl discloses that “Monoclonal antibodies recovered from these mice are comprised of bovine heavy chain variable domains paired in some cases with bovine kappa variable domains and in other cases with bovine lambda variable domains” (para. [0153]) and Wabl discloses the mice are “capable of producing an antibody with bovine V regions” (para. [0010]) which means that the bovine lambda variable domains are expressed and are therefore capable of being expressed as claimed.
Furthermore, regarding claim 1, it is noted that because the recited limitation of “is more likely to produce” is interpreted as an optional limitation (see claim interpretation above) and therefore this need not occur and is met by the rodent or cell disclosed by Wabl.
Additionally, regarding claim 1, concerning the limitation of “produces more,” as stated above (see claim interpretation above), this refers to all amounts of “more” production and includes natural variability in expression that would result in a slight increase in immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain and is therefore met by the mouse or cell of Wabl above.
Finally, regarding claim 1, concerning the wherein clause that the “transgenic rodent produces more, or is more likely to produce, immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain, as stated above, because Wabl discloses the structural limitations instant claims these properties are inherent to the rodent disclosed by Wabl.
Regarding claim 8, further to the discussion of claim 1 above, as stated above, Wabl discloses the engineered immunoglobulin locus comprises bovine Vλ (“an array of 25 bovine lambda variable
region gene segments (951), each comprised of bovine coding sequences embedded in mouse noncoding regulatory or scaffold sequences” para. [0135]; see also Examples 5-6) and Jλ gene segment coding sequences (“a 2 Kb piece of DNA containing the bovine Jλ, region gene segments embedded in mouse noncoding DNA (955)” para. [0135]; see also Examples 5-6) embedded in rodent non-coding regulatory or scaffold sequences of a rodent immunoglobulin K light chain variable region gene locus (“used in place of the K-K DNA” para. [0135] see also para. [0133] “carrying the deletion of
sequence in one of the two homologous copies of their immunoglobulin kappa chain locus”).
Regarding claim 12, further to the discussion of claim 1 above, Wabl discloses the transgenic mouse (which comprises transgenic mouse cells as discussed above) comprises one or more bovine Vλ gene segment coding sequences (“an array of 25 bovine lambda variable region gene segments, each comprised of bovine lambda coding sequences” para. [0148]) located upstream of one or more J-C units ((“an array of J-C units where each unit is comprised of a bovine J λ, gene segment and a mouse lambda constant domain gene segment”; para. [0148]; see Figure 10) wherein each J-C unit comprises a bovine Jλ gene segment coding sequence (“the bovine Jλ gene segments are those encoding J1, J2, J6 and 17” para. [0148]) and a rodent Cλ gene segment coding sequence (“the mouse lambda constant
domain gene segments are C1 and/or C2 and/or C3” para. [0148]) and rodent Cλ non-coding sequences (this disclosed embodiment is in the rodent λ locus and therefore comprises the remaining rodent Cλ non-coding sequences in addition to the coding sequences).
Regarding claim 28, further to the discussion of claim 1 above, although Wabl is silent to whether the engineered bovine immunoglobulin light chain locus comprises a rodent intronic K enhancer (iEK) and 3 'EK regulatory sequences, Wabl discloses the engineered bovine immunoglobulin light chain locus is the mouse K chain locus (para. [0133, 0135]: Figures 2-11; Example 4).
Regarding claim 28, Inlay evidences the mouse K chain locus comprises intronic K enhancer (iEK) and 3 'EK regulatory sequences (“Two enhancers have been identified within the κ loci: one within the Jκ-Cκ intron (iEκ) and the other ∼9-kb downstream of Cκ (3′Eκ)” pg. 463 col. 1 2nd para.).
Therefore, regarding claim 28, the mouse K chain locus disclosed by Wabl comprises the intronic K enhancer (iEK) and 3 'EK regulatory sequences.
Regarding claim 29, further to the discussion of claim 1 above, Wabl discloses the transgenic rodent or rodent cell comprises an engineered partly bovine immunoglobulin heavy chain locus comprising bovine immunoglobulin heavy chain variable region gene coding sequences and rodent non-coding regulatory or scaffold sequences of the rodent immunoglobulin heavy chain locus (“Upon introduction of the appropriate recombinase (604), the partly bovine immunoglobulin locus (629) is integrated into the genome upstream of the endogenous non-bovine constant region genes (627), resulting in the genomic structure illustrated at 631” para. [0099]; Figure 6; see in particular Example 3 and Figure 8) (“10 DH and 4 JH bovine coding sequences” Example 6; para [0155]).
Regarding claim 30, further to the discussion of claims 1 and 29 above, Wabl discloses the
engineered bovine immunoglobulin heavy chain locus comprises bovine VH (1-20 bovine VH coding regions), D and JH gene segments (“10 DH and 4 JH bovine coding sequences” Example 6; para [0155]).
Regarding claim 31, further to the discussion of claims 1 and 29-30 above, Wabl discloses each bovine VH, D or JH coding gene segment comprises VH, D or JH coding sequence embedded in rodent noncoding regulatory or scaffold sequences of the rodent immunoglobulin heavy chain locus (“is integrated into the genome upstream of the constant gene region (1127) as shown at 1129” Example 6; Figure 11).
Regarding claim 32, further to the discussion of claims 1 and 29-31 above, Wabl discloses the heavy chain rodent non-coding regulatory or scaffold sequences are interspersed by functional ADAM6A (“upstream sequences may contain non-immunoglobulin genes, such as ADAM6 (FIG. 1)” para. [0019]; “the engineered partly bovine immunoglobulin locus further comprises one or more of an ADAM6 gene” para. [0024]; see also para. [0069]; Table 4; claims 19 and 30).
Regarding claim 33, further to the discussion of claim 1 above, Wabl discloses the rodent regulatory or scaffold sequences are part of the rodent locus which comprises intervening sequences including introns and enhancers) (para. [0051]; see also para . [0069] and “mouse intergenic and intronic sequences” para. [0073], “intervening sequences based on the endogenous non-bovine genome” para. [0099] and para. [0103, 0117, 0133, 0135, 0142, 0148]).
Regarding claim 35, further to the discussion of claim 1 above, Wabl discloses the rodent is a mouse or rat (“rodent, e.g., a mouse or a rat” para. [0032]; see also para. [0005, 0007-0008, 0016, 0024, 0027, 0039, 0046-0048, 0067, 0069, 0072-0073, 0083, 0094, 0095-0096, 0103, 0105-0111, 0113, 0117, 0120-0127, 0129, 0133, 0135, 0138-0144, 0147-0148, 0152-0155]; claim 17).
Regarding claim 37, further to the discussion of claim 1 above, Wabl discloses the rodent cell is a mouse or rat embryonic stem (ES) cell (“Mouse embryonic stem (ES) cells derived from C57B1/6NTac mice” para. [0126]; see also para. [0025-0027, 0031, 0056, 0061, 0090, 0094, 0096-0097, 0110-0111, 0113, 0115, 0117, 0119-0120, 0127, 0129-0130, 0133, 0137-0138, 0143-0148, 0151-0152]; claims 23-24).
Regarding claim 38, further to the discussion of claim 1 above, Wabl discloses a cell of B lymphocyte lineage obtained from the transgenic rodent (“cell of B lymphocyte
lineage from the transgenic rodent” para. [0024]) wherein the engineered immunoglobulin locus expresses a chimeric immunoglobulin heavy chain or light chain comprising a bovine variable region and a rodent immunoglobulin constant region (“expresses immunoglobulin chains comprised of bovine variable domains and rodent constant domains” para. [0024]).
Accordingly, Wabl anticipates instant claims.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 9-10 and 14-15 rejected under 35 U.S.C. 103 as being unpatentable over Wabl et al. (US-20170303517-A1; henceforth “Wabl”) in view of MacDonald et al. (WO-2013096142-A1; henceforth “MacDonald”) and Reilly et al. (Proc Natl Acad Sci U S A. 1984 Apr;81(8):2484-8.; henceforth “Reilly”).
The teachings of Wabl above are hereby incorporated in their entirety.
Regarding claims 9-10 and 14, further to the discussion of claim 1 above, although Wabl discloses the engineered immunoglobulin locus comprises a rodent immunoglobulin K locus in which one or more rodent VK gene segment coding sequences and one or more rodent JK gene segment coding sequences have been deleted (“the deletion of sequence in one of the two homologous copies of their immunoglobulin kappa chain locus” para. [0133, 0135]: Figures 2-11) and replaced by one or more bovine Vλ gene segment coding sequences (“an array of 25 bovine lambda variable region gene segments (951), each comprised of bovine coding sequences embedded in mouse noncoding regulatory or scaffold sequences” para. [0135]) and one or more Jλ gene segment coding sequences (“a 2 Kb piece of DNA containing the bovine JA, region gene segments embedded in mouse noncoding DNA” (para. [0135]), respectively (see “L-K” para. [0135]; See also Example 4) (instant claims 9 and 14) and Wabl teaches rodent CK coding sequences with rodent C λ1, C λ2, C λ3 coding sequence (“the mouse lambda constant domain gene segments are C1 and/or C2 and/or C3” para. [0148]), Wabl is silent to a rodent λ constant region coding sequence in the K locus (instant claim 9) and Wabl is silent to replacing rodent CK coding sequences in the locus with rodent C λ2 coding sequence (instant claims 10 and 14).
Nevertheless, regarding claims 9-10 and 14, MacDonald teaches a transgenic rodent (mouse) or rodent cell comprising an engineered immunoglobulin light chain locus comprising a non-rodent (human) λ light chain variable region gene segments and a mouse Cλ2 domain (Cλ2 gene; para. ;0246]) in a kappa light chain locus (“a genetically modified mouse is provided that expresses a Vλ region on a CL that is a CK” para. [00246-00247]; “a genetically modified mouse is provided that expresses a hVλ region on a mouse CK” para. [00247]; see also para. [00101, 00246, 00288, 00293, 00305, 00309-00310, 00358, 00545-00546, 00565, 00691]; claims 42-44 and 28).
Additionally, regarding claims 9-10 and 14, Reilly teaches rearrangement of λ light chain sequences is more restricted that K chains (abstract), and that each of the Cλ gene segments is paired with a unique Jλ segment (pg. 2484 col. 1; see also pg. 2487 col. 1 last para. and col. 2 1st para.).
Therefore, regarding claims 9-10 and 14, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the mouse of Wabl, and simply substitute the known prior art element of the mouse Cλ2 constant domain of MacDonald for the endogenous mouse kappa constant domain of Wabl to obtain the predictable result of a mouse with a mouse Cλ2 constant domain in the kappa locus. One of ordinary skill would have been motivated to do so as taught by Reilly because recombination is more restricted for λ light chain sequences and substituting the Cλ2 constant domain of MacDonald would allow λ light chain variable sequences to recombine with Jλ segments. Regarding the reasonable expectation of success, Wabl evidences preparation of a transgenic mouse with λ sequences in the mouse λ chain locus (para. [0135]); Examples 4-6; Figures 10-11; see also claims 1-2).
Regarding claim 15, further to the discussion of claims 1 and 14 above, as stated above (see claims 9-10 and 14 rejection above), Wabl in view of MacDonald and Reilly make obvious substituting the mouse Cλ2 constant domain of MacDonald for the endogenous mouse kappa constant domain of Wabl which would result in the claimed configuration of the bovine Vλ gene segment coding sequences upstream of one or more bovine Vλ gene segment coding sequences which are upstream of one or more rodent Cλ coding sequences.
Hence, the claimed invention as a whole was prima facie obvious.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Non-Statutory Double Patenting
U.S. Patent No. 10793829
Claims 1, 8, 12, 28-33, 35 and 38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4 and 7-8 of US patent No. 10793829 (Henceforth “Wabl2”) as evidenced by Inlay et al. (Nat Immunol. 2002 May;3(5):463-8. Epub 2002 Apr 22.; henceforth “Inlay”).
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method for transgenic mouse of the cited patent anticipates or makes obvious the transgenic mouse of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claim 1, Wabl2 claims a transgenic rodent (mouse) (claim 1) or rodent (mouse) cell (claims 1-2 since rodents comprise rodent cells) comprising a genome comprising an engineered partly bovine immunoglobulin light chain locus comprising bovine immunoglobulin light chain variable region gene segments (“VH, DH and JH and/or bovine VL and JL coding Sequences”; claim 1).
Regarding claim 1, one of ordinary skill would at once envisage λ light chain variable region gene segments from the limited genus bovine VL (claim 1) which included λ or K gene segments.
Regarding claim 1, Wabl2 claims the locus “is functional and expresses immunoglobulin chains comprised of bovine variable domains and mouse constant domains” (claim 1), and the mouse is therefore capable of expressing immunoglobulin comprising bovine variable domains as claimed.
Regarding claim 1, it is noted that because the recited limitation of “is more likely to produce” is interpreted as an optional limitation (see claim interpretation above) and therefore this need not occur and is met by the rodent or cell claimed by Wabl2.
Additionally, regarding claim 1, concerning the limitation of “produces more,” as stated above (see claim interpretation above), this refers to all amounts of “more” production and includes natural variability in expression that would result in a slight increase in immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain and is therefore met by the mouse or cell claimed by Wabl2 above.
Finally, regarding claim 1, concerning the wherein clause that the “transgenic rodent produces more, or is more likely to produce, immunoglobulin comprising λ light chain than immunoglobulin comprising K light chain, because Wabl2 claims the structural limitations instant claims these properties are inherent to the rodent claimed by Wabl2.
Regarding claim 8, further to the discussion of claim 1 above, Wabl2 claims the engineered immunoglobulin locus comprises bovine light chain variable sequences embedded in mouse immunoglobulin variable gene locus non-coding regulatory and/or scaffold sequences (claim 1).
Regarding claim 8, one of ordinary skill would at once envisage the K gene locus from the limited genus of in mouse immunoglobulin variable gene locus claimed by Wabl2, which includes the 2 options of λ or K locus.
Regarding claim 12, further to the discussion of claim 1 above, as stated above, one of ordinary skill would at once envisage bovine V λ gene segment coding sequences from the limited genus of claimed light chain variable sequences.
Regarding claim 12, although Wabl 2 doesn’t directly claim the mouse, which comprises cells, includes J-C units comprises which comprise a bovine Jλ gene segment coding sequence and a rodent Cλ gene segment coding sequence and rodent Cλ non-coding sequences, Wabl discloses a method of making the claimed mouse, which comprises introducing J-C units comprising a bovine JL gene segment coding sequence from which one of ordinary skill would at once envisage a bovine Jλ gene segment coding sequence from the two options of λ or K into the mouse endogenous λ locus which comprises Cλ gene segments and mouse C λ non-coding sequences (claim 7) and therefore it would have been obvious to make the mouse with the claimed components in view of the method of making as claimed by Wabl2.
Regarding claim 28, further to the discussion of claim 1 above, one of ordinary skill would at once envisage the K from the limited genus of mouse immunoglobulin variable gene locus claimed by Wabl2 which includes the two options of the K or λ locus.
Regarding claim 28, Inlay evidences the mouse K chain locus comprises intronic K enhancer (iEK) and 3 'EK regulatory sequences (“Two enhancers have been identified within the κ loci: one within the Jκ-Cκ intron (iEκ) and the other ∼9-kb downstream of Cκ (3′Eκ)” pg. 463 col. 1 2nd para.).
Therefore, regarding claim 28, the mouse light chain locus claimed by Wabl2 comprises the intronic K enhancer (iEK) and 3 'EK regulatory sequences.
Regarding claim 29, further to the discussion of claim 1 above, Wabl2 claims the engineered partly bovine immunoglobulin heavy chain locus comprises bovine immunoglobulin heavy chain variable region gene coding sequences (bovine immunoglobulin variable gene VH; claim 1) and rodent non-coding regulatory or scaffold sequences (“mouse immunoglobulin variable gene locus non-coding regulatory and/or scaffold sequences”; claim 1) of the mouse immunoglobulin heavy chain locus (one of ordinary skill would at once envisage the heavy chain locus from the limited genus of “mouse immunoglobulin variable gene locus” which includes the two options of heavy or light chain).
Regarding claims 30-31, further to the discussion of claims 1 and 29 above, Wabl2 claims the
engineered bovine immunoglobulin heavy chain locus comprises bovine VH, D and JH gene segments (claim 1) (instant claim 30), embedded in mouse noncoding regulatory or scaffold sequences (“mouse immunoglobulin variable gene locus non-coding regulatory and/or scaffold sequences” claim 1) (instant claim 31).
Regarding claim 32, further to the discussion of claims 1 and 29-31 above, Wabl2 claims the heavy chain rodent non-coding regulatory or scaffold sequences are interspersed by functional ADAM6 genes (claim 4), from which one would at once envisage ADAM6a or ADAM6b genes as claimed.
Regarding claim 33, further to the discussion of claims 1 and 29-32 above, as stated above (see claim 28 above), Inlay evidences the mouse light chain locus claimed by Wabl2 comprises the intronic K enhancer (iEK) and 3 'EK regulatory sequences which are enhancer sequences.
Regarding claim 35, further to the discussion of claim 1 above, as stated above, Wabl2 claims the rodent is a mouse (claim 1).
Regarding claim 37, further to the discussion of claim 1 above, although Wabl2 does not claim a mouse embryonic stem (ES) cell with the claimed features, Wabl2 claims a method of making the mouse as claimed using a mouse a mouse embryonic stem (ES) cell (claim 8), and it would therefore be obvious to prepare the claimed cell.
Regarding claim 38, further to the discussion of claim 1 above, Wabl2 claims A cell of B lymphocyte lineage obtained from the transgenic mouse (claim 2), which expresses immunoglobulin chains comprised of bovine variable domains and rodent constant domains (claim 1).
Since the instant application claims are anticipated by or obvious over cited patent claims, said claims are not patentably distinct.
Claims 9-10 and 14-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4 and 7-8 of US patent No. 10793829 (Henceforth “Wabl2”) in view of MacDonald et al. (WO-2013096142-A1; henceforth “MacDonald”) and Reilly et al. (Proc Natl Acad Sci U S A. 1984 Apr;81(8):2484-8.; henceforth “Reilly”).
The teachings of Wabl2 above are hereby incorporated in their entirety.
The subject matter claimed in the instant application is disclosed in the referenced patent as
follows: the method for transgenic mouse of the cited patent makes obvious the transgenic mouse of instant application.
Although the claims at issue are not identical, they are not patentably distinct for the reasons stated below.
Regarding claims 9-10, further to the discussion of claims 1 and 8 above, as stated above (see claim 1 rejection above), one or ordinary skill would at once envisage the bovine λ gene segment coding sequences.
However, regarding claims 9-10, Wabl2 does not directly claim the engineered immunoglobulin variable region locus comprises J-C units wherein each J-C unit comprises a bovine Jλ gene segment coding sequence and a rodent λ constant region coding sequence (instant claim 9), where the mouse rodent constant region is a Cλ2 coding sequence (instant claim 10).
Nevertheless, regarding claims 9-10, Wabl2 claims a method for generating the mouse, which comprises a mouse cell, comprising integrating into a mouse genome upstream of an endogenous immunoglobulin variable gene locus which is the K locus (the endogenous immunoglobulin variable locus comprises VK and JK gene segments which means is a K locus; claim 7) and providing a vector comprising engineered partly bovine immunoglobulin locus comprising partly bovine immunoglobulin variable region segments comprising bovine VL and JL coding sequences (from which one of ordinary skill would at once envisage λ segments from the limited genus of two options of the K or λ segments) and it would therefore be obvious to prepare the claimed mouse with the bovine λ segments in the K locus.
Further, regarding claims 9-10, MacDonald teaches a transgenic rodent (mouse) or rodent cell comprising an engineered immunoglobulin light chain locus comprising a non-rodent (human) λ light chain variable region gene segments and a mouse Cλ2 domain (Cλ2 gene; para. ;0246]) in a kappa light chain locus (“a genetically modified mouse is provided that expresses a Vλ region on a CL that is a CK” para. [00246-00247]; “a genetically modified mouse is provided that expresses a hVλ region on a mouse CK” para. [00247]; see also para. [00101, 00246, 00288, 00293, 00305, 00309-00310, 00358, 00545-00546, 00565, 00691]; claims 42-44 and 28).
Additionally, regarding claims 9-10, Reilly teaches rearrangement of λ light chain sequences is more restricted that K chains (abstract), and that each of the Cλ gene segments is paired with a unique Jλ segment (pg. 2484 col. 1; see also pg. 2487 col. 1 last para. and col. 2 1st para.).
Therefore, regarding claims 9-10, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the mouse as claimed by Wabl2, and simply substitute the known prior art element of the mouse Cλ2 constant domain of MacDonald for the endogenous mouse kappa constant domain of Wabl2 to obtain the predictable result of a mouse with a mouse Cλ2 constant domain in the kappa locus. One of ordinary skill would have been motivated to do so as taught by Reilly because recombination is more restricted for λ light chain sequences and substituting the Cλ2 constant domain of MacDonald would allow λ light chain variable sequences to recombine with Jλ segments. Regarding the reasonable expectation of success, MacDonald evidences preparation of transgenic mice with edited K loci (Examples 2 and 10).
Regarding claims 14-15, further to the discussion of claims 1 and 8 above, although as stated above (see claims 9-10 rejection above, MacDonald and Reilly make obvious and provide a reasonable expectation of success for substituting the Cλ2 constant domain of MacDonald for the endogenous mouse kappa constant domain of Wabl2, which meets the claimed limitation of “rodent CK coding sequences in the locus have been replaced by rodent Cλ2 coding sequence” (instant claim 14), and the claims of Wabl2 include bovine Vλ gene segment coding sequences and one or more Jλ gene segment coding sequences in the K locus for the reasons stated above (see claim 8 rejection above), Wabl2 does not claim directly claim one or more rodent VK gene segment coding sequences and one or more rodent JK gene segment coding sequences have been deleted and replaced by the bovine sequences.
Nevertheless, regarding claims 14-15, Wabl2 claims a method of making the claimed mouse which results in “replacement of the endogenous immunoglobulin variable gene locus with the engineered partly bovine immunoglobulin locus” (claim 7), and is would therefore be obvious to prepare the claimed mouse in this way which would result in the claimed limitation of “one or more rodent VK gene segment coding sequences and one or more rodent JK gene segment coding sequences have been deleted and replaced by the bovine sequences” in the suggested mouse in the claimed configuration (instant claim 15).
Since the instant application claims are anticipated by or obvious over cited patent claims, in view of MacDonald and Reilly, said claims are not patentably distinct.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632