DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on October 1, 2025 have been received and entered. Claim 1 has been amended, while claims 5-6, 18-20, 24-30 and 32 have been canceled. 1-4, 7-17, 21, 23, 31, 33-34, 37, 40, 46 and 47 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-4, 6-17, 20-21, 23 and 24 (group I) in the reply filed on June 10, 2025 is acknowledged.
Claims 31, 33-34, 37, 40, 46 and 47 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 June 10, 2025.
Priority
This application is a 371 of PCT/US20/36114 filed on 06/04/2020, which claims priority from US provisional application no 62/857,712 filed on 06/05/2019.
Claims 1-4, 7-17, 21 and 23 are under consideration.
Withdrawn- Claim Rejections - 35 USC § 112- Scope of enablement
Claims 1-4, 6-17, 20-21, 23 and 24 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), because the specification fails to provide an enablement for the full scope of the claimed invention. Applicants’ cancellation of claims 6, 20 and 24 renders their rejections moot. Applicant’s amendments to the claims limiting the scope indicated in previous office action obviates the basis of the rejection, therefore, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1-4, 6-7, 10, 21, 23 and 24 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bradley et al (WO2019008123, dated 01/10/2019, filed 7/05/2018, EFD, 7/7/2017, IDS). In view of Applicants’ amendment of base claims 1, introducing the limitation claim 20, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
New-Claim Rejections - 35 USC § 112- necessitated by amendments
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.
Claims 2-4, 7-17, 21 and 23 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. Claims 2-4, 7-17, 21 and 23 recite limitation directed to the germline genome of the genetically modified rodent that is broader than the genetically modified mouse of claim1. Claim 17 recites a broader rodent constant lambda gene that does not further limit the mouse constant lambda gene of claim1. 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. Appropriate amendments and/or clarification is required.
Maintained- 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.
Claims 1-4, 7-11, 17, 21, 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Bradley et al (WO2019008123, dated 01/10/2019, filed 7/05/2018, EFD, 7/7/2017, IDS), Macdonald (WO2011/163311, 11/29/2011) and Tiller et al (MABS, 2013, 445-470, IDS).
With respect to claims 1-3, 21 and 24, Bradley teaches a transgenic mouse whose genome comprises an engineered endogenous immunoglobulin kappa light chain locus comprising a rearranged human Vλ, hJλ and hCλ genes knocked in at the endogenous kappa locus (Fig. 1), wherein the locus is homozygous or alternatively, is heterozygous (lines 1-2 on page 28). It is further disclosed that the constant region can be mouse C lambda (page 22, 26, line 7), wherein the expression of the endogenous lambda chain is inactivated (lines 19-21, page 27) (limitation of claim 21), and wherein the transgenic mouse can be produced using the ES cells comprising said engineered endogenous immunoglobulin kappa light chain locus (lines 10-11 on page 50) and wherein said mouse is used for the production of bi-specific antibody (see pages 4-7, and examples 5-9).
Regarding claim 4, Bradley teaches that the mouse further comprises unrearranged heavy chain variable region genes comprising (in 5' to 3' direction) (a) one or more VH gene segments; (b) one or more DH gene segments; (c) one or more JH gene segments; and (d) a heavy chain constant region encoding one or more CH domains (lines 20-24 on page 32, claim 21 of ‘123), the human heavy chain variable region genes are incorporated into the IgH locus (lines 1-3 on page 13), an endogenous enhancer is used (lines 1-2 on page 25)
With respect to claims 7 and 10, Bradly specifically discloses hVλ3-21 and hJλ3 (see D1, example 1).
With respect to claim 23, Bradley teaches that the engineered endogenous immunoglobulin k light chain locus further comprises endogenous enhancers at their endogenous location in the endogenous immunoglobulin k light chain locus (see page 25, lines 1-2).
Bradley differs from claimed invention by not disclosing. that (i) wherein the human immunoglobulin l light chain variable region is in place of one or more rodent Vk gene segments, one or more rodent Jk gene segments and (ii) the human Vλ gene segment comprises Vλ1-51 or Vλ2-14 and human Jλ gene segment comprises Jλ2.
Macdonald teaches all or substantially all endogenous mouse light chain variable region gene segments could be replaced with one or more human λ variable region gene segments (see para. 13). It is further disclosed that the κ locus comprises at least one hVλ and at least one hJλ, and lacks or substantially lacks a functional Vκ region gene segment and lacks or substantially lacks a functional Jκ region gene segment. In one embodiment, the mouse comprises no functional Vκ region gene segment. In one embodiment, the mouse comprises no functional Jκ region gene segment (see para. 44) (limitation of claim 20). Macdonald discloses the replacement of murine Vk and Jk with human Vl and Jl operatively linked with murine Ck or Cl (see para. 8-9).
With respect to claim 17, Macdonald teaches mouse Cλ gene is at least 80%, at least 90%, at least 95%, 96%, 97%, 98%, or at least 99% identical to mouse Cλ2 (see para. 51).
The combination of references differs from claimed inventio by not dislcosing human Vλ gene segment comprises Vλ1-51 or Vλ2-14 and human Jλ gene segment comprises Jλ2.
Before the effective filing date of instant application, Tiller cures the deficiency by disclosing human Vλ gene segment comprises Vλ1-51 or Vλ2-14 and human Jλ gene segment comprises Jλ2 that preferentially associates with human heavy variable domain (see fig. 3 and page 465, col. 2).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art of Bradley by selecting hVl.2-14 and hVl 1-51 as light chain segment as suggested in Tiller, with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art recognized that hVl.2-14 and hVl 1-51 are preferentially associated with human heavy variable domain (see Figure 3). Given that insertion, replacement and/or deletion of a gene segment from a immunoglobulin heavy and/or light chain locus were routinely used to produce genetically modified mouse engineered with genetic material encoding human antibodies, in whole or in part, it would have been a matter of design choice for one of ordinary skill in the art to combine and select hVl.2-14 and hVl 1-51 as light chain variable gene segment each of which is taught by the prior art to be useful for the same purpose in order to produce new genetically modified mouse as claimed. One of skill in the art would have had a reasonable expectation of success in combining the teachings of prior art because it was routine in the art before filing of instant application to produce reverse chimeric antibodies over fully human antibodies in mouse as suggested by Bradley and Macdonald. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art at the time of the invention.
Claims 12-15 remain rejected under 35 U.S.C. 103 as being unpatentable over Bradley et al (WO2019008123, dated 01/10/2019, filed 7/05/2018, EFD, 7/7/2017), Macdonald (WO2011/163311, 11/29/2011) and Tiller et al (MABS, 2013, 445-470). as applied above for claim 1 and 4 and further in view of Lee al (WO2015/049517, 04/09/2015) as evidenced by Bradley et al (2, US20120204278A1).
The teaching of Bradley, Macdonald and Tiller have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that the one or more unrearranged human VH gene segments, one or more unrearranged human DH gene segments, and one or more unrearranged human JH gene segments are in place and/or replace one or more endogenous VH gene segments one or more endogenous DH gene segments, one or more endogenous JH gene segments, or a combination thereof.
Lee et al teach a genetically modified mouse whose germline genome comprises an engineered endogenous immunoglobulin k light chain locus comprising human VA and JA gene segments and a human Cl gene. The engineered endogenous immunoglobulin k light chain locus further comprises a mouse Cl gene (figure 1). It is further disclosed that FACS analysis of splenic B cells from the Pl homozygotes showed no detectable mouse Cx expression (Fig. 2).
Lee et al teach mouse genome further comprises an immunoglobulin heavy chain locus comprising human VH gene segments comprising human V, D and J gene segments (see page 22, lines 26-29). Specifically, Murphy discloses immunoglobulin heavy chain locus comprising one or more human V gene segments, one or more human D gene segments and one or more human J gene segments upstream of a mu constant region of said mouse; endogenous heavy chain expression has been substantially inactivated; and the heavy chain locus comprises an Eu enhancer of mouse (see page 30, lines 13-17, page 40, lines 9-17). It is further disclosed that the he one or more human VH gene segments comprise VH2-5, VH7-4-1, VH4-4, V H1-3, VH1-2, VH6-1, or any combination thereof, (11) the one or more human DH gene segments comprise DH1-1, DH2-2, DH2-15, DH3- 16, DH4-17, DH6-19, DH1-20, DH2-21, DH3-22, DH6-25, DH1-26, DH7-27, or any combination thereof, and (iii) the one or more human JH gene segments comprise JH1, JH2, JH3, JH4, JH5, JH6, or any combination thereof (see page 63-64, table 1). Bradley provided the guidance that endogenous immunoglobulin variable heavy/light region locus can be replaced with a homologous or orthologous human variable heavy/light region locus (see para. 139)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art of Bradley to modify the mouse whose germline genome comprises an engineered endogenous immunoglobulin light chain locus comprising human V and J gene segments and a human C gene as disclosed by further incorporating an immunoglobulin heavy chain locus comprising human VH gene segments as suggested by Lee and Bradley (2), with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to inactivate endogenous mouse C gene in order to ensure the exclusive production of lambda chains. Further, one of ordinary skill in the art would be motivated to replace endogenous variable gene segment with corresponding human variable gene segment as art recognized the obvious advantages of reverse chimeric antibodies over fully human antibodies in mouse (supra). Given that insertion, replacement and/or deletion of a gene segment from a immunoglobulin heavy and/or light chain locus were routinely used to produce genetically modified mouse engineered with genetic material encoding human antibodies, in whole or in part, it would have been a matter of design choice for one of ordinary skill in the art to combine different compositions each of which is taught by the prior art to be useful for the same purpose in order to produce new genetically modified mouse as claimed. One of skill in the art would have had a reasonable expectation of success in combining the teachings of prior art because it was routine in the art before filing of instant application to produce reverse chimeric antibodies over fully human antibodies in mouse as suggested by Lee and Bradley. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art at the time of the invention.
Claim 16 remains rejected under 35 U.S.C. 103 as being unpatentable over Bradley et al (WO2019008123, dated 01/10/2019, filed 7/05/2018, EFD, 7/7/2017), Macdonald (WO2011/163311, 11/29/2011) and Tiller et al (MABS, 2013, 445-470). as applied above for claim 1 and 4 and further in view of Macdonald (2, WO2013096142, dated 6/27/2013)
The teaching of Bradley, Macdonald and Tiller have been described above and relied in same manner here. The combination of references differs from claimed invention by not disclosing he germline genome of the genetically modified rodent comprises one or more nucleotide sequences encoding one or more rodent ADAM6 polypeptides, functional orthologs, functional homologs, or functional fragments thereof.
Macdonald (2) teaches the insertion of the ADAM6 sequence to restore fertility after immunoglobulin gene modification (see para. 179,721-723 and claim1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art seeking to produce a mouse who genome comprises in its germline a human V, J operably linked to mouse C gene segments at endogenous kappa light chain locus would be motivated to combine the teachings of prior art of Bradley by incorporating ADAM6a in the genome of said mouse as suggested in Macdonald (2), with a reasonable expectation of success, before the effective filing date of instant application. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to do so because prior art recognized insertion of the ADAM6 sequence restore fertility after immunoglobulin gene modification (supra). One of skill in the art would have had a reasonable expectation of success in combining the teachings of prior art prior art recognized that incorporation of exogenous ADAM6 sequence after modification of endogenous immunoglobin locus as suggested in Macdonald. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396).
Response to arguments
Applicant disagree with the rejection arguing that the exemplified focus of the '123 publication is rearranged human a light chain, specifically those rearranged from IGLV3-21 *01 and IGLJ3*02 (see Example 1). Applicant assert that essentially, the '123 publication lists both possible light chain loci (lambda and kappa) and then lists all options of human, mouse or rat light chain constant regions. However, the '123 application docs not lead one of ordinary skill in the art to create an engineered endogenous immune globulin K light chain locus as presently claimed, and pointing to the disclosure that the constant region can be mouse C lambda is cherry picking from a list of options. Additionally, at the kappa locus, the teachings of Macdonald focus on unrearranged human Vk and human Jk gene segments with a mouse CK gene, further indicating that one of ordinary skill in the art would not be led combine the '123 publication and Macdonald to achieve the pending claims. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant’s argument in part relying on example 1, it should be noted that the disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). To the extent, applicant in part agree that ‘123 teaches a finite number of all the options of human, mouse or rat light chain constant region, it is applicable to the rejection. As stated in previous office action, the rejection in part relies on that KSR that states “only in the case of an infinite number of variants, it is a specific set of variant non-obvious.” That is not the case here (emphasis added). The teaching in the cited art of record is limited to a finite number of mouse constant gene.
Macdonald teaches a mouse is provided that comprises a rearranged light chain gene that comprises a human "kappa variable sequence linked to a mouse constant region sequence; in one embodiment, the mouse constant region sequence is a lambda constant sequence (see para. 8). Given that one of ordinary skill in the art was well aware that the ratio of kappa to lambda light chain usage in humans is about 60:40, whereas in mice it is about 95:5 and the results to generate compatible V domains. In fact, Macdonald describes many advantages of expressing binding proteins derived from human Vl and Jl gene segments in mice by placing human l sequences at an endogenous light chain locus, for example, the mouse kappa locus. Antibodies made from such mice can have light chains that comprise human Vl domains fused to a mouse CL region, specifically a mouse CK or C l region. The mice will also express human V l domains that are suitable for identification and cloning for use with human CL regions, specifically CK and/or Cl regions. Because B cell development in such mice is otherwise normal, it is possible to generate compatible Vl domains (including somatically mutated Vl domains) in the context of either C l or CK regions (see page 188). In response to applicant’s argument that Macdonald focus on unrearranged human Vl and human Jl gene segments with a mouse CK gene, it should be noted that it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. It also appears that applicant is attempting to attack each reference individually. However, in a 103 rejection the references must be considered as a whole. In the instant case, Macdonald functionally discloses the replacement concept of removing c kappa with C lambda at the endogenous kappa locus forcing lambda usage. Absent evidence of any unexpected and/or superior results. It would have been obvious for one of ordinary skill in the art reviewing the teaching of Macdonald would recognize that in mouse kappa dominates (about 95%) and lambda is rare and an artisan seeking for lambda antibodies would be motivated to replace/use C kappa with C lambda at the kappa locus as disclosed in Bradley for kappa rearrangement that would occur at the kappa locus but the expressed light chain would be lambda. Further, the art further teaches that this would occur under normal kappa regulatory control resulting in lambda expression thereby also avoiding kappa/lambda competition and mixed light chain, with reasonable expectation of success, before the effective filing date of the instant invention. .
On page 11 of the applicant's argument, applicant re-iterates and rely on their previous arguments pertaining that have been discussed in preceding section. The arguments are substantially the same as those addressed in the foregoing response.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Bradley (US9445581) teaches a nonhuman mammal (mouse) whose genome comprise: a plurality of human IgH V regions, one or more human D regions and one or more human J regions upstream of the host non-human mammal constant region;] one or more human Ig light chain kappa V regions and one or more human Ig light chain kappa J regions upstream of the host non-human mammal kappa constant region, and one or more human Ig light chain lambda V regions and one or more human Ig light chain lambda J regions downstream of the host non-human mammal (mouse) lambda constant region, optionally in which the human lambda variable region may be inserted upstream or downstream of the endogenous host lambda locus in operable linkage with a human lambda constant region, such that the non-human mammal (mouse) can produce fully human antibody light chains and chimeric heavy chains.
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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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632