DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
1. Claims 1-12 have been cancelled.
Claims 13-22 are pending and under examination.
Claim Rejections - 35 USC § 103
2. 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.
3. 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 than 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
4. The applicant argues that none of the references teaches or suggests the ranges of 11-36 and 5-36 V[Symbol font/0x6B] gene segments recited in the claims.
However, there is no requirement for the prior art to specifically teach the recited ranges. The rejection states that Foster teaches 32 productively rearranged Vĸ gene segments, a value which is inside the recited ranges, thus meeting these limitations in the claims. The appellant did not point to anything indicating or suggesting that a value falling within a claimed range is not enough to render the claimed range obvious
The applicant argues that none of the references teaches or suggests the 11 specific V[Symbol font/0x6B] or the 18 VH gene segments recited in the claims.
This is not found persuasive for the reasons set forth in the rejection. Briefly, the claimed V[Symbol font/0x6B] gene segments are among the 32 functional Vĸ gene segments taught by Foster; the claimed VH gene segments are among the 30 functional VH gene segments taught by Brezinschek. The 32 Vĸ and 30 VH gene segments fall within the scope of the claims.
The applicant argues that nothing in Foster supports additionally excluding the 7 genes present at a frequency of ˂ 1% in the productive arrangement.
This is not found persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The teaching in Foster that 7 genes rearrange at the very low frequency of ˂ 1% would suggest to one of skill in the art that these genes do not make a significant contribution to the human antibody repertoire. Excluding them would have been obvious. MPEP 2141.03 states:
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
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The "hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art." Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988).
And even assuming that one of skill in the art would not have excluded the 7 genes productively rearranged at a frequency of ˂ 1%, one of skill in the art would have still used the 32 productively rearranged gene segments, a value falling within the scope of the claims.
With respect to the argument regarding anticipation, the rejection did not and does not state that the ranges are anticipated. Just because in the reply to arguments the examiner inadvertently stated that the ranges are anticipated does not automatically change the statutory basis of the rejection from 35 USC 103 to 35 USC 102.
The applicant argues that Foster makes no suggestion regarding which Vĸ gene segments could be used in Buelow’s transgenic rodents.
This is not found persuasive for the reasons above. Foster’s teachings would suggest to one of skill in the art to only use the productively rearranged Vĸ gene segments.
Furthermore, Foster does not have to teach transgenic animals. Both Buelow and Jakobovitz provide evidence that the human Vĸ gene segments could be successfully used in transgenic animals. Thus, one of skill in the art would have reasonably expected to be successful in obtaining transgenic animals expressing the Vĸ gene segments taught by Foster. Apart from an argument, the applicant did not provide any evidence to the contrary.
The arguments addressing Jakobovitz are not found persuasive because the rejection states it is Brezinschek (not Jakobovitz) teaches that the human B cell only utilize about 30 functional VH genes to generate the antibody repertoire; these genes include all human VH genes recited in the instant claims.
It is true that Jakobovitz’s transgenic animal comprises a transgenic locus (yH2)
containing 66 human VH genes. However, Jakobovitz teaches that, out of the 66 VH
genes found on yH2, only 37 are functional. Jakobovitz teaches that the transgenic
animal utilizes at least 11 out of these 37 functional VH genes (see paragraph bridging
p. 36 and 37 and Table III). The teaching of “at least” in Jakobovitz suggests that the
data presented in Table III is not exhaustive and that the transgenic animal could utilize
more than 11 functional VH genes. Thus, Jakobovitz provides the suggestion to use
between 11 and 37 functional VH genes, not 66 or more VH genes as argued by the
appellant.
Importantly, Jakobovitz teaches that the VH gene utilization by the transgenic
animal is similar to the VH genes usage in humans as taught by Brezinschek (see p. 37,
lines 4-13; p. 48, lines 10-15). Thus, Jakobovitz considers Brezinschek pertinent to
obtaining transgenic animals capable of producing humanized antibodies. One of skill
in the art would have looked at Brezinschek for guidance in identifying additional
functional VH genes which could be used in transgenic animals to obtain a repertoire
resembling the human antibody repertoire.
Brezinschek teaches that about 30 VH functional genes are used in humans to
generate the antibody repertoire and thus, using these genes to obtain the transgenic
animal would have been obvious to one of skill in the art. The genes disclosed by Brezinschek include the 11 VH genes identified by Jakobovitz (compare Jakobovitz’s Table III with Brezinschek’s Table V) and all VH genes recited in the claims.
Thus, the combined teachings of Jakobovitz and Brezinschek render using the
claimed VH genes prima facie obvious.
The applicant argues that Jakobovitz deleted a section of the germline genes, which includes the claimed L6, L8, and L12.
However, there is nothing in Jakobovitz teaching or even suggesting against using the L6, L8, and L12 V[Symbol font/0x6B] gene segments, especially in view of de Wildt and Foster teaching that these gene segments are used to generate the human antibody repertoire. While Jakobovitz’s focus was on specific proximal V[Symbol font/0x6B] gene segments (see paragraph bridging p. 32 and 33), there is nothing in Jakobovitz to discourage from using L6, L8, and L12. Table IV in Jakobovitz discloses that O2, L5, A20, O8, L1, A30, B3, and A27 are used by the transgenic mice for antibody rearrangement. All of these gene segments are listed by de Wildt and Foster as belonging to the most frequently used V[Symbol font/0x6B] genes in the human repertoire (see Fig. 1 on p. 896 in de Wildt; see Table IV on p. 1617 in Foster). Jakobovitz provides evidence for a reasonable expectation of success that the genes of de Wildt and Foster would be utilized by the transgenic rodent to make humanized antibodies representing the human repertoire.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
5. THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILEANA POPA whose telephone number is (571)272-5546. The examiner can normally be reached 8:00 am to 4:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
