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 1-100, 102-114, 117-120 have been canceled. Claims 101, 115, 116 remain pending.
Specification
The title will have to be changed to more closely reflect the fact that the claims are drawn to a genetically modified mouse that makes a humanized antibody, specifically that has a humanized immunoglobulin light chain sequence and an inactivated IgG1 gene.
Election/Restrictions
Applicants elected Group I, claims 101,103,105-108,113, without traverse in the reply filed on 4-17-23.
Claims 115 and 116 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 4-17-23.
Claim 101 remains under consideration.
Applicant's arguments filed 6-26-25 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.
Claim objection
The formatting of item 1) of claim 101 is acceptable and allowable. Support is described on pg 9-12 of the response filed 6-26-25.
Claim Rejections - 35 USC § 112
Written Description
Claim 101 remains 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.
Withdrawn rejections
The rejection regarding gene segments that “rearrange, and form a human Ig VH gene [segment] that is operably linked to the endogenous IgG1 constant gene” in a B-cell (end of item A) or the structure/function of the light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments in item B) of claim 101 has been withdrawn in view of the amendment filed 6-26-25. Item 1) of claim 101 as newly written has support as set forth on pg 9-12 of the response filed 6-26-25.
The rejection regarding the phrase “wherein the genetically modified mouse expresses:… …an increase in the titer of antigen specific single domain antigen binding proteins in response to antigen challenge compared to a similar mouse that is capable of producing single domain antigen binding proteins but that does not express the human Ig x light chain variable domain operably linked to the Ig light chain x constant domain” has been withdrawn because the concept has been deleted.
Pending rejection
A) The specification lacks written description for a mouse whose germline genome comprises the “single Ig light chain” of item 2) in claim 101.
Claim 101 is drawn to
A genetically modified mouse whose germline has a genome that comprises:
(1) a replacement of:
i) a plurality of unrearranged endogenous immunoglobulin (Ig) variable heavy chain (VH) gene segments,
ii) all unrearranged endogenous Ig diversity heavy chain (DH) gene segments, and
iii) all unrearranged endogenous Ig joining heavy chain (JH) gene segments, with:
a) a plurality of unrearranged human Ig variable heavy chain (VH) gene segments, and
b) all unrearranged human Ig diversity heavy chain (DH) gene segments, and
c) all unrearranged human Ig joining heavy chain (JH) gene segments,
such that the unrearranged human Ig VH, DH, and JH gene segments are operably linked to an endogenous IgG1 gene that comprises a deleted or inactivated nucleotide sequence encoding its CH1 domain, wherein the unrearranged human Ig VH, DH, and JH gene segments rearrange in a B cell such that the mouse functionally expresses:
an IgG1 antibody comprising a human heavy chain variable domain operably linked to an endogenous IgG1 with a deleted or inactivated CH1 domain; and
(2) a single Ig light chain encoded from a single rearranged VL:JL sequence operably linked to a light chain constant region, wherein the single Ig light chain is expressed before the IgG1 antibody comprising the human heavy chain variable domain operably linked to the endogenous IgG1 with the deleted or inactivated CH1 domain.
Pg 45, para 135, describes a “universal light chain mouse” with a single rearranged variable gene sequence VL:JL and generation of antigen specific antibodies in 13/022,759, 13/093,156, 13/412,936, 13/488,628, 13/798,310, and 13/948,818 (Publication Nos. 2011/0195454, 2012/0021409, 2012/0192300, 2013/0045492, US20130185821, and US20130302836.
Example 2 (pg 59) describes replacement of:
a plurality of [unrearranged] endogenous variable heavy chain (VH) gene segments,
all endogenous diversity heavy chain (DH) gene segments, and
all endogenous mouse joining heavy chain (JH) gene segments
with
a plurality of unrearranged human light chain variable kappa (Vκ) gene segments, and
all human light chain joining kappa (Jκ) gene segments--- (Fig. 15 and 16). The mouse has an inactivated endogenous IgG1 CH1 domain, IgG2b CH1 domain, and IgG2a CH1 domain, while leaving the endogenous IgM, IgD, IgG3, IgE, and IgA genes (Fig. 16).
Fig. 16 is limited to inactivating the endogenous IgG1 CH1 domain, the IgG2b CH1 domain, and the IgG2a CH1 domain, while leaving the endogenous IgM, IgD, IgG3, IgE, and IgA genes intact. Pg 36 indicates the IgG1 and IgM must remain functional and the specification contemplates inactivating the CH1 domain of endogenous IgM, IgG1, IgA, IgE, and IgD (pg 12, last 3 lines through pg 13, line 2.
The specification lacks written description for the genome of a mouse comprising “a single Ig light chain” as required in claim 101 because genomes are nucleic acids and Ig light chains are proteins.
The specification lacks written description for any Ig light chain encoded by a “rearranged VL: JL sequence” in the germline genome of a mouse as required in claim 101 because this requires rearrangement which occurs only in B-cells of the mouse.
The specification lacks written description for any “single” Ig light chain encoded by “single rearranged VL: JL sequence” in the germline genome of a mouse as required in item 2), lines 1-2, of claim 101 because any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement. A B-cell within the mouse may have a “single” rearrangement of VL/JL gene segments, but the mouse does not have a “single” rearrangement as claimed.
The specification lacks written description for expressing a “single” Ig light chain after rearrangement of VL/JL gene segments as required in item 2), line 3, of claim 101 because any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement. A B-cell within the mouse may have a “single” rearrangement of human VL/JL gene segments, but the mouse does not express a “single” rearrangement of human VL/JL gene segments as claimed.
Item 2) relates to the “universal light chain mouse” with a rearranged variable gene sequence VL:JL and generation of antigen specific antibodies in 13/022,759, 13/093,156, 13/412,936, 13/488,628, 13/798,310, and 13/948,818 (Publication Nos. 2011/0195454, 2012/0021409, 2012/0192300, 2013/0045492, US20130185821, and US20130302836; however, the structures/functions associated with those mice are completely missing from the claim. All of these patent applications relate to replacing endogenous mouse light chain variable and joining gene segments with human light chain gene segments. Accordingly, the specification lacks written description for a mouse whose genome comprises the concept in item 2) without a genetic modification or replacement of endogenous VL and JL gene segments with human VL and JL gene segments.
The specification lacks written description for B-cells expressing an Ig light chain “before the IgG1 antibody” [of item (1)] as required in item (2) of claim 101. Support cannot be found and none can be found. The term “before” occurs on pg 16, para 50, and 57, para 176, but not in context of when light vs. heavy chains are expressed.
The specification does not teach the structure of the rearranged VK1-39JK5 or VK3-20JK1 gene segments as encompassed by item 2) of claim 101. It is unclear whether the VK1-39, JK5, VK3-20, or JK1 gene segments lack their endogenous recombination signal sequences (RSS) (pg 9, para 24; pg 23, para 74) or if they retain their endogenous RSS as encompassed by item 2) of claim 101.
The specification lacks written description for the structure of the rearranged light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments that gives it the function of a “universal light chain” as encompassed by item 2) of claim 101. Pg 45, para 135, says the universal light chain (ULC) “causes expansion of antibodies at the early IgM stage, where the bulk of the diversity and thus antigen recognition occurs on the heavy chain. Without limitation as to the invention, it is proposed that expansion at the early IgM stage with a genetically engineered single rearranged light chain will result in more cells that bear the heavy or light chain variable regions capable of surviving to undergo class-switching to an IgG isotype and selection in the context of an IgG that lacks a functional C1 domain or that lacks a functional C1 domain and lacks a functional hinge region”. The instant application provides no guidance regarding how to modify the RSSs (if necessary) to arrive at a ULC having the function described in paragraph 135, i.e. class switching. The instant application provides no guidance regarding the exact structure of a rearranged light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments that has the function of a ULC on pg 45. The specification does not teach how to “join” VK1-39 + JK5 or VK3-20+JK1 gene segments so that they have the function of a ULC described on pg 45. The specification does not teach how to make a rearranged light chain that contains VK1-39 + JK5 or VK3-20+JK1 gene segments that retain their RSSs as encompassed by item 2) of claim 101.
Accordingly, the specification lacks written description for item 2) of claim 101.
Response to arguments
Applicants’ discussion of “single Ig light chain” on pg 12, “temporal expression of a single Ig light chain” on pg 13-15 is noted, but item 2) of claim 101 does not begin to capture the structures/functions required for “universal light chain” mice for reasons set forth above. The claim says the germline “genome” of the mouse contains a “single Ig light chain”, but nucleic acids can’t contain a protein. The claim says it has a single Ig light chain, but each B-cell in the mouse under goes unique rearrangement and is capable of a multitude of VL/JL combinations. The discussion talks about replacing endogenous VL and JL gene segments with human VL and JL gene segments which is missing from the claim. The discussion talks about a “universal light chain” mouse, but this concept is missing from the claim.
Enablement
Claim 101 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for A genetically modified mouse whose germline has a genome comprising a replacement of:
i) a plurality of unrearranged endogenous variable heavy chain (VH) gene segments,
ii) all unrearranged endogenous diversity heavy chain (DH) gene segments, and
iii) all unrearranged endogenous joining heavy chain (JH) gene segments,
with:
a) a plurality of unrearranged human light chain variable kappa (Vκ) gene segments, and
b) all unrearranged human light chain joining kappa (Jκ) gene,
such that the unrearranged human heavy chain Vκ and Jκ gene segments are operably linked to a modified endogenous IgG gene that comprises a deleted or inactivated nucleotide sequence encoding its CH1 domain, wherein the unrearranged human Ig VH, DH and JH gene segments rearrange in a B cell such that the mouse functionally expresses:
an IgG1 antibody comprising a human heavy chain variable domain operably linked to an endogenous IgG1 with a deleted or inactivated CH1 domain.
(see patented claim in parent application),
does not reasonably provide enablement for item 2) of claim 101). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Withdrawn rejections
The rejection regarding gene segments that “rearrange, and form a human Ig VH gene [segment] that is operably linked to the endogenous IgG1 constant gene” in a B-cell (end of item A) or the structure/function of the light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments in item B) of claim 101 has been withdrawn in view of the amendment filed 6-26-25. Item 1) of claim 101 as newly written has support as set forth on pg 9-12 of the response filed 6-26-25.
The rejection regarding the phrase “wherein the genetically modified mouse expresses:… …an increase in the titer of antigen specific single domain antigen binding proteins in response to antigen challenge compared to a similar mouse that is capable of producing single domain antigen binding proteins but that does not express the human Ig x light chain variable domain operably linked to the Ig light chain x constant domain” has been withdrawn because the concept has been deleted.
Pending rejection
A) The specification does not enable making/using a mouse whose germline genome comprises the “single Ig light chain” of item 2) in claim 101.
The claim and its scope, the teachings in the specification, and the examples are recited above.
The specification does not enable making/using the genome of a mouse comprising “a single Ig light chain” as required in claim 101 because genomes are nucleic acids and Ig light chains are proteins.
The specification does not enable making/using any Ig light chain encoded by a “rearranged VL: JL sequence” in the germline genome of a mouse as required in claim 101 because this requires rearrangement which occurs only in B-cells of the mouse.
The specification does not enable making/using any “single” Ig light chain encoded by “single rearranged VL: JL sequence” in the germline genome of a mouse as required in item 2), lines 1-2, of claim 101 because any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement. A B-cell within the mouse may have a “single” rearrangement of VL/JL gene segments, but the mouse does not have a “single” rearrangement as claimed.
The specification does not enable making/using expressing a “single” Ig light chain after rearrangement of VL/JL gene segments as required in item 2), line 3, of claim 101 because any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement. A B-cell within the mouse may have a “single” rearrangement of human VL/JL gene segments, but the mouse does not express a “single” rearrangement of human VL/JL gene segments as claimed.
Item 2) relates to the “universal light chain mouse” with a rearranged variable gene sequence VL:JL and generation of antigen specific antibodies in 13/022,759, 13/093,156, 13/412,936, 13/488,628, 13/798,310, and 13/948,818 (Publication Nos. 2011/0195454, 2012/0021409, 2012/0192300, 2013/0045492, US20130185821, and US20130302836; however, the structures/functions associated with those mice are completely missing from the claim. All of these patent applications relate to replacing endogenous mouse light chain variable and joining gene segments with human light chain gene segments. Accordingly, the specification does not enable making/using a mouse whose genome comprises the concept in item 2) without a genetic modification or replacement of endogenous VL and JL gene segments with human VL and JL gene segments as broadly encompassed by item 2) of claim 101.
The specification does not enable making/using B-cells expressing an Ig light chain “before the IgG1 antibody” [of item (1)] as required in item (2) of claim 101. Support cannot be found and none can be found. The term “before” occurs on pg 16, para 50, and 57, para 176, but not in context of when light vs. heavy chains are expressed.
The specification does not enable those of skill to determine the structure of the rearranged VK1-39JK5 or VK3-20JK1 gene segments as encompassed by item 2) of claim 101 and described in the specification. It is unclear whether the VK1-39, JK5, VK3-20, or JK1 gene segments lack their endogenous recombination signal sequences (RSS) (pg 9, para 24; pg 23, para 74) or if they retain their endogenous RSS as encompassed by item 2) of claim 101.
The specification does not enable those of skill to determine the structure of the rearranged light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments that gives it the function of a “universal light chain” as encompassed by item 2) of claim 101. Pg 45, para 135, says the universal light chain (ULC) “causes expansion of antibodies at the early IgM stage, where the bulk of the diversity and thus antigen recognition occurs on the heavy chain. Without limitation as to the invention, it is proposed that expansion at the early IgM stage with a genetically engineered single rearranged light chain will result in more cells that bear the heavy or light chain variable regions capable of surviving to undergo class-switching to an IgG isotype and selection in the context of an IgG that lacks a functional C1 domain or that lacks a functional C1 domain and lacks a functional hinge region”. The instant application provides no guidance regarding how to modify the RSSs (if necessary) to arrive at a ULC having the function described in paragraph 135, i.e. class switching. The instant application provides no guidance regarding the exact structure of a rearranged light chain comprising human VK1-39 + JK5 or VK3-20+JK1 gene segments that has the function of a ULC on pg 45. The specification does not teach how to “join” VK1-39 + JK5 or VK3-20+JK1 gene segments so that they have the function of a ULC described on pg 45. The specification does not teach how to make a rearranged light chain that contains VK1-39 + JK5 or VK3-20+JK1 gene segments that retain their RSSs as encompassed by item 2) of claim 101.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use a mouse whose germline genome comprised the “single Ig light chain” required in item 2) of claim 101.
Indefiniteness
Claim 101 remains 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.
Withdrawn rejection
The pending rejections have been withdrawn in view of the amendment.
New rejections
A) The concept of the germline genome of a mouse comprising “a single Ig light chain” in claim 101 makes the claim indefinite because genomes are nucleic acids and Ig light chains are proteins. A genome cannot comprise a protein as claimed.
The concept of an Ig light chain encoded by a “rearranged VL: JL sequence” in the germline genome of a mouse in claim 101 makes the claim indefinite. The metes and bounds of a “rearranged VL:JL” cannot be determined because it is not defined in the specification or the art at the time of filing. The concept also does not make sense because rearrangement of Ig gene segments occurs only in B-cells of the mouse and not in the genome of the mouse.
The concept of the genome of the germline in a mouse having a “single” Ig light chain encoded by “single rearranged VL: JL sequence” in item 2), lines 1-2, of claim 101 makes the claim indefinite. Any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement. They do not occur in the germline as claimed. A B-cell within the mouse may have a “single” rearrangement of VL/JL gene segments, but the germline genome of a mouse does not have a “single” rearrangement as claimed.
The concept of expressing a “single” Ig light chain after rearrangement of VL/JL gene segments in item 2), line 3, of claim 101 makes the claim indefinite. Any number of combinations of VL: JL can occur in B-cells of the mouse after rearrangement but not in the germline genome as claimed. B-cells, as a whole within the mouse, do not have a “single” rearrangement as claimed. Only a “single” B-cell within the mouse may have a “single” rearrangement of one human VL gene segment and one human JL gene segment.
The concept of the germline genome or B-cells of a mouse expressing an Ig light chain “before the IgG1 antibody” [of item (1)] as required in item (2) of claim 101 makes the claim indefinite. The term “before” occurs on pg 16, para 50, and 57, para 176, but not in context of when light vs. heavy chains are expressed. It is unclear whether expression of the Ig light chain before the humanized IgG1 is in response to contacting the mouse with an antigen or if it is a naturally occurring state that relates to part of the mouse’s development.
Macdonald (8754287) taught a mouse with a germline modification comprising an endogenous IgG constant region gene that has: a) a deletion of a CH1 domain; b) at least one human heavy chain variable gene segment, and c) an intact IgM constant region gene, wherein the mouse expresses an IgG comprising a human variable domain. The art at the time of filing did not reasonably teach or suggest a mouse with the genetic modification claimed.
Macdonald (10143186) taught a genetically modified mouse, but it does not appear to have the same structure or function as those in item B) of claim 101.
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.
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.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638