DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/30/2026 has been entered.
Claims 1-12 have been cancelled. Claims 21 and 22 are new.
Claims 13-22 are pending and under examination.
2. The double patenting rejection over claim 2 of U.S. Patent No. 11,877,565 is withdrawn in view of the terminal disclaimer filed on 01/30/2006, which was approved on 03/04/2026.
Claim Rejections - 35 USC § 103
3. 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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
4. Claims 13-22 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Buelow (PGPUB 2009/0098134), in view of all Jakobovitz et al. (WO 98/24893) and Brezinschek et al. (J. Immunol., 1995, 155: 190-202), Guglielmi et al. (BBA, 2003, 1642: 181-190), de Wildt et al. (J. Mol. Biol., 1999, 285: 895-901), and Foster et al. (J. Clin. Invest., 1997, 99: 1614-1627), as evidenced by Lefranc et al. (Exp. Clin. Immunogenet., 2001, 18: 161-174).
Buelow teaches a transgenic rodent comprising a transgene containing a heterologous human immunoglobulin heavy chain locus and a transgene comprising a heterologous human immunoglobulin light chain locus, wherein the transgenes are functional, undergo rearrangements, and produce a repertoire of humanized antibodies ([0011]; [0012]; [0017]-[0019]; [0048]; [0123]; [0155]; [0171]). Buelow teaches that the transgene comprising the heterologous human immunoglobulin heavy chain locus comprises human V, J, and D genes and rat constant region genes such as Cµ and C[Symbol font/0x67]. Buelow also teaches that the transgene comprising the heterologous human immunoglobulin light chain locus comprises human V genes and rat constant region genes such as C[Symbol font/0x6C] or C[Symbol font/0x6B] (see [0182]; [0184]; [0185]; [0188]) (claims 14 and 17). Buelow teaches using their transgenic rodent in a method of producing humanized monoclonal antibodies, as recited in claims 19 and 20 (see [0083]; [0085]; [0087]-[0089]; [0093]-[0094]). Since Buelow teaches isolating and using nucleic acids encoding monoclonal antibodies (see [0089]; [0092]), one of skill in the art would have found obvious to identify antibodies by cloning the immortalized B-cells and sequencing the variable regions of the heavy and light chains. One of skill in the art would also have found obvious to obtain monoclonal antibodies of interest by re-cloning the identified sequences into an expression vector and introducing this vector into producer cells (claim 20). Although Buelow does not specifically teach using all six human J genes (claim 14), doing so was practiced in the prior art (see Jakobovitz et al., p. 5, lines 4-5; Fig. 1); thus, using all six human J genes would have been obvious to one of skill in the art with the reasonable expectation of obtaining a transgenic rodent suitable to be used for the production of humanized monoclonal antibodies. Since Jakobovitz et al. teach that mice can be used to generate humanized antibodies (see p. 5), one of skill in the art would have found obvious to modify Buelow’s teachings by specifically using a mouse as the transgenic rodent (claim 18).
Buelow does not specifically teach the human VH genes recited in claims 14 and 22. However, using these genes is suggested by the prior art. For example, Jakobovitz et al. teach that including an array of VH and V[Symbol font/0x6B] gene segments leads to enhanced antibody specificity and affinity against a wide variety of antigens (see Abstract; p. 5; p. 16, lines 24-26; p. 20, lines 6-25). Brezinschek et al. teach that human B cell only utilize about 30 functional VH genes to generate the antibody repertoire, wherein the 30 genes include all human VH genes recited in the instant claim 14 (see Abstract; p. 193, column 1, last paragraph and column 2; p. 194, Table III; p. 196, Table V). Based on these teachings, one of skill in the art would have known that only a limited number of VH genes are required to generate the human antibody repertoire. One of skill in the art would have found obvious to modify Buelow by using the 30 functional VH genes taught by Brezinschek et al. to achieve the predictable result of obtaining a transgenic rodent capable of generating a diversity of humanized antibodies with enhanced specificity and affinity against a wide variety of antigens, wherein the diversity of humanized antibodies resembles the human antibody repertoire.
Buelow, Jakobovitz et al., and Brezinschek et al. do not specifically teach a murine LCR (claim 14) and B-cell specific regulatory elements. Guglielmi et al. teach including the murine heavy chain LCR and the B cell-specific Eµ intronic enhancer to achieve enhanced and strict expression in B-cells at all stages of maturation (see Abstract; p. 181; p. 182, column 2, first paragraph; p. 189, column 2, last paragraph). One of skill in the art would have found obvious to further include the LCR and the Eµ intronic enhancer to achieve the predicable result of obtaining enhanced transgene expression in B-cells.
With respect to claims 15 and 16, Jakobovitz et al. teach that the VH segments can be encoded by the same transgene comprising a dominant selective marker or by different transgenes (see Examples 2 and 3). With respect to the limitation of different selective markers recited in claim 16, one of skill in the art would have found obvious to use different selective markers to ensure that all heterologous heavy and light chain loci are present in the non-human transgenic mammal.
Buelow, Jakobovitz et al., Brezinschek et al., and Guglielmi et al. do not specifically teach the V[Symbol font/0x6B] genes recited in claims 13, 14, 21, and 22. de Wildt et al. and Foster et al. teach that the functional human V[Symbol font/0x6B] genes include the genes recited in claims 13 and 14. Specifically, de Wildt et al. teach that A17, O12, A19, A20, A27, L2, L6, O18, L8, L12, and B3 are among the most productively rearranged V[Symbol font/0x6B] genes (see p. 895; p. 896, Fig. 1; p. 899, paragraph bridging columns 1 and 2). Foster et al. teach that 30 V[Symbol font/0x6B] genes (including A17, O12, A19, A20, A27, L2, L6, O18, L8, L12, and B3) are productively rearranged to produce the human antibody repertoire. Foster et al. teach that only the productively arranged genes are translated into functional proteins. While Foster et al. teach that 39 genes considered potentially functional were found in both productive and nonproductive rearrangements, Foster et al. disclose that 7 were actually not found in the productive rearrangements and 7 were found to be represented significantly less that predicted (˂ 1%) (see p. 1614, column 2; paragraph bridging p. 1614 and 1615; p. 1617, Table IV and column 2). Based on these teachings, one of skill in the art would have readily understood that only the productively-arranged genes are needed to generate antibodies and would have found obvious to further modify the teachings of Buelow, Jakobovitz et al., Brezinschek et al., and Guglielmi et al. by using the 32 functional human V[Symbol font/0x6B] genes taught by de Wildt et al. and Foster et al. to achieve the predictable result of obtaining a transgenic rodent capable of generating a diversity of antibodies with enhanced specificity, wherein the diversity of antibodies resembles the human antibody repertoire. Further excluding the 7 genes present at a frequency of ˂ 1% in the productive arrangement would have also been obvious to one of skill in the art. As evidenced by Table 3 in Lefranc et al., A17, O12, A19, A20, A27, L2, L6, O18, L8, L12, and B3 genes disclosed by de Wildt et al. and Foster et al. are the V[Symbol font/0x6B] genes 2-30, 1-39, 2-28, 1-27, 3-20, 3-15, 3-11, 1-33, 1-9, 1-5, and 4-1, respectively, as recited in claims 13 and 14. By following the teachings and suggestions in the prior art, one of skill in the art would have arrived at the claimed transgenic non-human mammals where the human V[Symbol font/0x6B] gene segments consist of 32 human gene segments (including V[Symbol font/0x6B]2-30, V[Symbol font/0x6B]1-39, V[Symbol font/0x6B]2-28, V[Symbol font/0x6B]1-27, V[Symbol font/0x6B]3-20, V[Symbol font/0x6B]3-15, V[Symbol font/0x6B]3-11, V[Symbol font/0x6B]1-33, V[Symbol font/0x6B]1-9, V[Symbol font/0x6B]1-5, and V[Symbol font/0x6B]4-1) and the human VH genes consist of 30 segments (including VH1-69, VH4-59, VH3-53, VH3-49, VH4-34, VH3-48, VH3-33, VH3-30, VH3-23, VH1-18, VH3-15, VH4-39, VH1-8, VH3-05, VH2-5, VH4-4, VH1-2, and VH6-1) as recited in claims 13, 14, 21, and 22.
Thus, the claimed invention was prima facie obvious at the time it was made.
Response to Arguments
5. The arguments addressing Foster are not found persuasive for the reasons set forth in the rejection. Foster actually teaches 32 (not 39) productively rearranged Vĸ genes, which include the claimed Vĸ genes and thus anticipates the claimed ranges of 11-36/5-36, regardless of whether the claims recite “comprise”/“consist”. Reciting “consist” does not change the fact that the new claims recite a range and that any value falling within the claimed range anticipates the range.
The cited prior art teaches a transgenic rodent comprising Vĸ gene segments where the Vĸ gene segments consist of 32 human Vĸ gene segments that comprise V[Symbol font/0x6B]2-30, V[Symbol font/0x6B]1-39, V[Symbol font/0x6B]2-28, V[Symbol font/0x6B]1-27, V[Symbol font/0x6B]3-20, V[Symbol font/0x6B]3-15, V[Symbol font/0x6B]3-11, V[Symbol font/0x6B]1-33, V[Symbol font/0x6B]1-9, V[Symbol font/0x6B]1-5, and V[Symbol font/0x6B]4-1, as required by the new claims 21 and 22. Thus, the new claims 21 and 22 are rendered obvious by the cited prior art.
For these reasons, the argument that none of the references discloses or suggests the 11 specific human Vĸ gene segments recited in the claims is not found persuasive.
The argument that Foster, de Wildt, and Girschick do not include the claimed Vĸ gene segments in the top 11 Vĸ gene segments is not found persuasive because this is not a claim requirement. Importantly, based on the teachings in the cited prior art, one of skill in the art would have still used the claimed 11 Vĸ gene segments regardless of whether they are taught as being among the top 11 or not.
For the same reasons, the argument addressing Brezinschek is not found persuasive.
The argument that the top five genes in de Wildt are lambda and not kappa gene segments is not material to the rejection, which is not based on lambda gene segments.
The argument that Foster is not pertinent art was addressed in the Advisory Action. While the applicant must be aware, that the examiner stated “antibody fragments” was clearly an inadvertent error. This does not take away from the fact that Foster is pertinent art.
The arguments addressing Jakobovitz are not found persuasive because the rejection states it is Brezinschek (not Jakobovitz) who teaches the 30 functional VH gene segments.
6. No claim is allowed. No claim is free of prior art.
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/ILEANA POPA/Primary Examiner, Art Unit 1633