DETAILED ACTION
Claims 1-2, 4-5, 7-10, 12-14, 16-19, and 21-25 are currently pending in this application. The present application is being examined under the pre-AIA first to invent provisions. An action on the merits follows.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/25/24, 1/28/25, 5/2/25, and 7/1/25 are in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements have been considered by the examiner, and initialed and signed copies of the 1449s are attached to this action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) and 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, provisional Application No. 61/133,274, filed on 6/27/08, hereafter referred to as the provisional ‘274 application, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, the provisional ‘274 application does not disclose making a library of cells as currently claimed, a library of cells made using such a method, or the use of any such library of cells to produce antibodies or for use a screening method, wherein each cell of the library comprises nucleic acids that encode at least two separate heavy chain variable regions having different target epitopes, comprising transfecting and allowing for integrating into the genome of said cells nucleic acid sequences encoding said at least two heavy chain variable regions and selecting for successful integration, wherein said nucleic acids encode heavy chain variable regions encoded by nucleic acids comprised in B cells of a transgenic non-human animal that has been immunized with the antigen, wherein the genome of the transgenic animal comprises a transgene comprising a human immunoglobulin light chain germline V gene segment fused to a human immunoglobulin light chain germline J gene segment such that there is no mutation due to said fusion, wherein the fused human V/J gene segments encode a rearranged human immunoglobulin light chain variable region and wherein the transgene comprises a light chain constant region gene segment or is operatively linked to an endogenous light chain constant region gene segment and wherein said transgenic animal produces a population of B cells producing antigen- specific antibodies, wherein said antibodies comprise the rearranged human light chain immunoglobulin variable region encoded by the fused human V/J gene segments paired with a diversity of heavy chain variable regions. While the provisional ‘274 application does disclose making transgenic animals, specifically mice, whose genome has been modified to comprise an expression cassette comprising a rearranged human V/J sequence and encoding a human light chain variable region sequence, and further discloses obtaining B cells from said mice, the provisional ‘274 application does not disclose introducing at least two nucleic acid sequences encoding heavy chain sequences derived from B cells of an immunized transgenic mouse into a single cell, either alone or in combination with a nucleic acid sequence encoding the same single human variable region expressed by the transgenic mouse, or further does not disclose a library of such cells as recited in instant claims 1-2, 4-5, 7-10, 12-14, and 16-19. The provisional ‘274 application further does not disclose the use of such a library for screening as recited in instant claims 21-23 or the method of producing a composition and composition made thereby in claims 24-25 which are based on the use of the library of cells. As such, all of claims 1-2, 4-5, 7-10, 12-14, 16-19, and 21-25 are denied benefit of priority under 37 U.S.C. 119(e) to provisional application 61/133,274.
In addition, the disclosures of the prior-filed applications, Application No. 12/589,181, filed on 10/19/09, hereafter referred to as the ‘181 application, and Application No. 12/459,285, filed on 6/29/09, hereafter referred to as the ‘285 application, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, neither the ‘181 application nor the ‘285 application provide support for a library of cells as claimed wherein the at least two nucleic acids sequences encoding heavy chain variable regions present in each cell are under the control of different regulatory elements, and/or are expressed at different levels in the cell as recited in instant claims 4 or 13, and claims 5 or 14 respectively. In addition, neither the ‘181 application nor the ‘285 application disclose the “provision” of sequences for site directed integration of at least two nucleic acid sequences encoding heavy chain variable regions in cells of the library as claimed in claims as recited in instant claims 8 and 9 and 17-18. Furthermore, neither the ‘181 application or the ‘285 application disclose screening a library comprising performing a bioassay measuring antagonistic activating activity as recited in instant claims 22-23. The first disclosure of the subject matter recited in instant claims 4-5, 8-9, 13-14, 17-18, and 22-23 appears in the claims filed on of the filing of Application No. 15/863,787, which was filed on 1/5/18. As such, claims 4-5, 8-9, 13-14, 17-18, and 22-23 are denied benefit of priority to either of the ‘181 or ‘285 applications under 35 U.S.C. 120.
Based on the above analysis, the effective filing date for the claim is as follows: claims 1-2, 7, 10, 12, 16, 19, 21, and 24-25 are entitled by benefit of priority under 35 U.S.C. 120 to an earliest effective filing date of 6/29/09 based on the filing date of Application No. 12/459,285; and claims 4-5, 8-9, 13-14, 17-18, and 22-23 are entitled by benefit of priority under 35 U.S.C. 120 to an earliest effective filing date of 1/5/18 based on the filing date of Application No. 15/863,787.
Claim Rejections - 35 USC § 112
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 8-9, 17-18, and 22-25 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 pre-AIA the applicant regards as the invention.
Claim 8 depends on claim 1 and recites the limitation, “wherein sequences for site directed integration of said nucleic acid sequences encoding said heavy chain variable regions are provided”. The phrase “are provided” is to sequences for site directed integration is confusing as it is unclear how and when such sequences are “provided” to the cell. Claim 17 depends on claim 2 which depends on claim 1 and recites the same limitation as claim 8. Claim 1 recites the method step, “transfecting and allowing for integrating into the genome of said cells nucleic acid sequences encoding said at least two heavy chain variable regions”. It is unclear whether the sequences for site directed integration of said nucleic acid sequences encoding said heavy chain variable regions are delivered prior to the transfection of the cells-i.e. the cells already comprise sequences for site directed integration of said nucleic acid sequences encoding said heavy chain variable regions, or whether the sequences of site directed integration are provided concurrently with, or subsequent to the transfection of the cells with the sequences encoding the at least two heavy chain variable regions, or whether the sequences encoding the at least two heavy chain variable regions further comprises the sequences for site directed integration of said nucleic acid sequences encoding said heavy chain variable regions. Therefore, the metes and bounds of the structure of the cells present library before and after transfection cannot be determined, and as such both claims 8 and 17 are considered indefinite. Claims 9 and 18 depend on claims 8 and 17 respectively and are therefore included in this rejection.
Claim 9 and claim 18 are further indefinite in that it is unclear as to which sequences are being referred to in the limitation, “wherein said sequences are for homologous recombination”. Claim 9 depends on claim 8. Claim 18 depends on claim 17. Claim 8 and claim 17 each recite two different sequences such that the recitation of “said sequence” in claims 9 and 18 is confusing as it is unclear which sequence is being referenced.
Claim 22 depends on claim 19 and recites the step, “performing a bioassay measuring said antagonistic activating activity”. It is unclear what is meant by “antagonistic activating activity”. The terms “antagonistic” and “activating” are in conflict in this phrase as they indicate opposing activity where a molecule which is “antagonistic” prevents the activity of or inactivates its target molecule as opposed to activating the target molecule. The preamble of the claim recognizes this difference as it cites that the method is for identifying a cell producing antibodies “that antagonize or activate a function of a molecule”. The specification does not recite the phrase “antagonistic activating activity” and further does not specifically disclose the concept of an antibody which antagonizes the function of a target molecule or disclose any bioassay for measuring a antagonistic activating activity of any antibody. As such, the definition of “ antagonistic activating activity” cannot be determined and the metes and bounds of both the phrase itself, and the bioassay for measuring any such “antagonistic activating activity” cannot be determined. Claim 23 depends on claim 22 and thus is included in this rejection. In the interests of compact prosecution, claims 22-23 have given their broadest reasonable interpretation as involving the use of bioassay which can measure either antagonistic or activating activity of an antibody on a target molecule comprising the target epitope.
Claim 23 depends on claim 22 and recites the step, “further comprising transferring said nucleic acids encoding said at least two separate heavy chain variable regions and nucleic acid encoding said light chain variable region into a production cell. However, claim 22 is a method for identifying a cell producing antibodies and recites contacting a library of claim 19, which is a library of cells where each cell comprises nucleic acids that encode at least two heavy chain variable regions and a rearranged human light chain variable region, with different target epitopes and screening for and selecting a cell expressing heavy chain variable regions recognizing said target epitopes. As such, claim 23 read as whole incorporating the limitations of the claims 22 and 19 upon which it depends recites two different sets of nucleic acids encoding at least two separate heavy chain variable regions where the first set is the nucleic acids encoding a least two separate heavy chain variable regions contained the cells of the library, and the second set is nucleic acids which have been selected a recognizing target epitopes. Therefore, the recitation in claim 23 of “said at least two separate heavy chain variable regions” is confusing and indefinite as it is unclear whether applicant is referring to the unselected nucleic acids or selected nucleic acids. Claims 24 and 25 depend on claim 23 and thus are included in this rejection. In the interests of compact prosecution, claims 23-25 have been given their broadest reasonable interpretation of encompassing either the unselected nucleic acids or the selected nucleic acids.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-5, 7-10, 12-14, 16-19, and 21-25 are 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 an immunized transgenic mouse whose genome comprises a transgene encoding a single rearranged human immunoglobulin light chain variable region comprising, wherein the sequence encoding the rearranged human variable region is operatively linked to a light chain constant region gene segment present in the transgene, or to an endogenous constant region gene segment, B cells obtained from the immunized transgenic mouse, and nucleic acid sequences encoding heavy chain variable region obtained from the B cells of the transgenic mouse, does not reasonably provide enablement for making and using any transgenic non-human animal whose genome comprises the claimed transgene further comprising a constant region from any non-human animal, or which is operatively linked to an endogenous constant region gene segment from a non-human animal. 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 or use the invention commensurate in scope with these claims.
The claims read on methods of producing a library of cells, a library of cells produced by the methods, and methods of using the library of cells to produce antibodies or to screen for antibodies. All claims depend on independent claim 1 which includes the limitation that the nucleic acid sequences encoding at least two heavy chain variable regions which are integrated into each library cell are encoded by nucleic acids comprised in B cells of a transgenic non-human animal, wherein the genome of the transgenic non-human animal comprises a transgene comprising a human immunoglobulin light chain germline V gene segment fused to a human immunoglobulin light chain germline J gene segment such that there is no mutation due to said fusion, wherein the fused human V/J gene segments encode a rearranged human immunoglobulin light chain variable region and wherein the transgene comprises a light chain constant region gene segment or is operatively linked to an endogenous light chain constant region gene segment and wherein said transgenic animal produces a population of B cells producing antigen- specific antibodies, wherein said antibodies comprise the rearranged human light chain immunoglobulin variable region encoded by the fused human V/J gene segments paired with a diversity of heavy chain variable regions. The claims thus encompass a genus of non-human transgenic animals which include millions of species including insects, amphibians, invertebrates -both aquatic and land based, avians, fish, and mammals. The specification, however, only provides specific guidance for generating transgenic mice, and further provides specific guidance for transgenes comprising a single human V gene segment fused to a single J gene segment and encoding a single rearranged human light chain variable region and wherein the rearranged V-J genes are operably linked either to a mouse or human constant region present in the transgene, or are site-specifically inserted into the mouse genome into the kappa light chain locus such that the V-J sequence present in the transgene is operably linked to the endogenous kappa light chain constant region gene. The specification clearly teaches that the purpose of the transgenic non-human animals, specifically mice, is the generation of human/humanized antibodies. The specification discloses that other non-human mammals may be generated, including rats, but provides no specific guidance for preparing a transgenic rat or any other non-human animal of any species. The working examples are limited to the generation and use of transgenic mice whose genome comprises a transgene encoding a single rearranged human kappa V gene segment where the transgene comprises a human IGVK1-39 gene sequence fused to a human JK gene segment and operably linked to a murine constant region gene, where the transgene lacks the MoEki enhancer and/or contains a truncated mouse 3’ kappa enhancer, where the transgene has been inserted into a mouse ES cell which is then implanted into a surrogate female mouse. Thus, the specification, while broadly teaching the generation of non-human animals with a targeted insertion into an immunoglobulin locus, provides no specific guidance for generating a targeted insertion into the genome of any other non-human animal. The specification does not disclose ES cells from any species of animal other than the mouse, or provide alternative methods to generate a knockin genotype in the genome of a non-huma animal which do not rely on the use of ES cells which are manipulated in vitro and are capable of contributing to the germline of an animal.
At the time of filing, the technology to produce animals with a gene-targeted knockout or knockin was considered limited to transgenic mice because the available technology used homologous recombination in embryonic stem (ES) cells, and at the time of invention only mouse ES cells were available for the production of transgenic mice by homologous recombination. This is because only mouse ES cells were known to be able to colonize the germ line. Clark et al., states "despite intensive efforts, knockout technology is limited to mouse as germline competent ES cells have not been developed for other species of mammals" (Clark et al. (2003) Nature Reviews: Genetics. Vol. 4, 825-833, page 828, col. 1, para. 1, lines 18-21). This is further supported by Niemann et al. who assert that the "true ES cells, those able to contribute to the germ line, are only available from inbred mouse strains" (Niemann et al (2005) Rev. Sci, Tech. Off. Int. Spiz. Vol. (24), 285-298, pages 290 last para. bridging to page 291, para.1). Niemann further emphasizes that ES-like cells and primordial germ cells have been reported for several farm animal species without germ line contribution (page 291, col. 1, lines 5-9). Likewise, Wheeler states ES cells have been isolated from several species including Syrian golden hamster, rat, rabbit, mink, pig, cow, sheep and primate, but the totipotency, the ability to colonize the germ line, awaits validate in the form of transgenic offspring (Wheeler (2001) Theriogenology. Vol. 56, 1345-1369, page 1351, para. 1). Prelle et al. states many attempts have been made to establish ES and EG cell lines from species other than mouse; however, there is no data that these cells can colonize the germ line of chimeric animals (Prelle et al. (2002) Anat. Histol. Embryol., Vol. 31, 169-186, see page 172, col. 1, lines 1-11). Finally, Munoz et al. teaches that even as of 2009 ES cells lines from animals other than mouse and human had yet to be established due to difficulties in the isolation and maintenance of ESC lines from other species (Munoz et al. (2009) Stem Cell Rev. and Rep., Vol. 5, 6-9, pages 6 and 9). Thus, the art of record clearly establishes that at the time of filing, of non-human animal species, only mouse ES cells were known to colonize the germ line, and therefore, the prior art at the time of filing only provides support for the production of knockin mice using mouse ES cells.
In addition, at the time of filing it was well known that not all animal species share the same or equivalent immunoglobulin loci structure or functions. Flajnik et al., for example, teaches that there are substantial differences in antibody loci structure, the classes and structure of antibody generated, and the mechanism of producing antibody diversity between placental mammals, avians, amphibians, and various fish (Flajnik et al. (2002) Nat. Rev., Vol. 2, 688-698). Flajnik further teaches that while certain vertebrates including several mammals utilize gene conversion for generating diversity- referred to as GALT species by Flajnik, which include chickens, rabbits, and cows, many other mammals, including mice and humans, utilize rearrangement and somatic hypermutation for generating antibody diversity (see Flajnik, Table I). Thus, the art at the time of filing establishes that there are substantial differences in antibody loci structure, the classes and structure of antibody generated, and the mechanism of producing antibody diversity not only between disparate animal such as mammals, avians, amphibians, and various fish, but that such structural and mechanistic divergence is observed even between various mammalian species. As such, the skilled artisan would not have been able to predict without undue experimentation whether a rearranged human variable region sequence would be able to functionally join with any constant region sequence and be further able to pair with any endogenous cognate variable region sequence.
Thus, due to the art recognized substantial differences in Ig loci and diversity generation between humans and mice and other animals, including other mammals, the lack of specific guidance in the specification for inserting transgenes into the genomes of animals other than mice, the lack of availability at the time of filing for ES cells capable of contributing to the germ line of any non-human animal other the mouse, the limitation of the working examples to the generation of knock-in transgenic mice using mouse ES cells, and the breadth of the claims, it would have required undue experimentation to make and use the scope of transgenic non-human animals as claimed , or to make and use the scope of nucleic acids encoding heavy chain variable regions present in B cells of the transgenic non-human animals as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 1 and 7-10 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by U.S. Patent Application Publication 2005/0170398 (2005), hereafter referred to as Van Berkel et al.
The following comments are made regarding claim construction and claim interpretation. There are two types of claims under rejection, the methods claims, claims 1 and 7-9, and the product claims, claim 10. In regards to the method claims, 1, and 7-9, these methods for producing a library of cells recite two active steps of “transfecting and allowing for integrating into the genome of said cells nucleic acid sequences encoding said at least two heavy chain variable regions and selecting for successful integration, where said nucleic acids encode heavy chain variable regions comprised in B cells of a transgenic non-human animal that has been immunized with the antigen”. As written, the two active steps are transfecting cells with the nucleic acid sequences, and selecting for successful integration of said sequences. The recitation of the phrase “where said nucleic acids encode heavy chain variable regions comprised in B cells of a transgenic non-human animal that has been immunized with the antigen” identifies that the heavy chain regions as the same as ones present in B cells of the transgenic animal, but does not actually limit the method to a step of obtaining the nucleic acid from the actual B cells which themselves have been obtained from the recited transgenic non-human animal. The method claim limitations are met as long as the nucleic acids used to transfect the cells encode the same/equivalent heavy chain regions which are present in the transgenic non-human animal. The at least two nucleic acids encoding two separate heavy chain variable regions read on any at least two isolated nucleic acids which encode heavy chains that are the same/equivalent as those present in B cells of the transgenic non-human animals. The claims do not further limit the heavy chains in terms of specific V, D, J gene segments, any specific sequences, or any specific antigen reactivity-i.e. a specific antigen(s) or antigenic epitope(s). Further, the rearranged heavy chain variable regions derived from B cells present in an immunized transgenic animal as claimed are not required to pair with the exact transgenic rearranged light chain recited as the transgenic rearranged light chain variable region VJ sequence is subject to somatic hypermutation. Furthermore, since the transgenic non-human animal encompasses embodiments where the endogenous light chain loci are both intact, there is in fact no requirement that the heavy chains that are present in B cells of the transgenic non-human animal be limited to those that pair with the introduced rearranged human light chain variable region versus a rearranged endogenous light chain. As such, the claimed methods read on obtaining nucleic acids which encode heavy chain variable regions from any source as long as the encoded heavy chain is the same/equivalent to ones present in B cells of the transgenic non-human animal described, which include heavy chains that pair either with an introduced rearranged light chain variable region which may or may not have undergone somatic hypermutation, or heavy chains that pair with any one or more endogenous rearranged light chains, which again may or may not have undergone somatic hypermutation. Turning to the product claim, claim 10 is a product by process claims, where the library of cells is “obtainable” by the method of claim 1. Please note that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). In the instant case, the source of the at least two human heavy chain variable region encoding nucleic acid sequences does not change the actual structure of the human heavy chain. Thus, the structure of the product as claimed is a library of cells where each cell comprises at least two nucleic acids encoding a heavy chain variable region integrated into the genome of the cell. In regards to claim interpretation of a “library of cells”, it is noted that the instant specification does not provide a definition for what constitutes a “library” of cells. As such, the phrase “a library of cells” has been given its broadest reasonable interpretation, which is a population of cells in which each cell has a genome comprising the at least two heavy chain variable region encoding sequences.
Van Berkel et al. teaches a host cell stably transformed with nucleic acid sequences encoding a single common light chain variable region and at least 2, including 3, 4 ,5 ,6 ,7 ,8 , 9, and 10 or more, different nucleic acids encoding different heavy chain variable region sequences, where the 2 or more heavy chain variable regions sequence have specificity for different target antigens, or different epitopes within the same target antigen, where the heavy chain variable regions are expressed and secreted as IgG, IgA, or IgM, and where the heavy chains are fully human or chimeric (Van Berkel et al., paragraphs 18-19, 55-63, 95, and 97). Van Berkel et al. further teaches that the at least two different heavy chain may be expressed at different levels (Van Berkel et al., paragraph 22, 62, and 83). Van Berkel et al. also teaches that host cell can be cloned and that the population of clones, i.e. a library of clones, can be screened for the production of a mixture of antibodies having a desired effect (Van Berkel et al., paragraph 22, 62, and 81). Van Berkel et al. teaches to transform the host cells with vector(s) encoding the 2 or more heavy chain variable regions, where each heavy chain is encoded by a different vector or by the same vector, and where each vector comprises a promoter and other regulatory elements for driving expression of the encoded variable regions (Van Berkel et al., paragraphs 63-66). Van Berkel et al. also teaches a particular expression vector for expression of the heavy chain where the vector comprises the HAVT20 leader sequence which comprises a secretion signal peptide (Van Berkel et al., paragraph 115). Van Berkel et al. further teaches that the host cells are eukaryotic cells, or mammalian cells such as human cells (Van Berkel et al., paragraph 68). In particular, Van Berkel et al. teaches the use of the immortalized PER.C6.TM cell as the host cell (Van Berkel al., paragraphs 68 and 70). In addition, Van Berkel et al. teaches that the nucleic acid molecules encoding the single common light chain and the two or more heavy chains are stably integrated into the chromosome of the host cell, where the integration employs site-specific integration into a predetermined position in the genome of the cell by homologous recombination (Van Berkel et al., paragraph 69, and 99). Van Berkel et al. teaches the selection of stable PER.C6.TM cells comprising the two heavy chain sequences and the common light chain sequence integrated into the genome, i.e. transgenic stable clones (Van Berkel et al., paragraph 119 and 126). Van Berkel et al. also teaches that the nucleic acid molecules encoding the two or more heavy chain variable regions and the single light chain variable region can be obtained from in vivo immunization methods, or from in vitro antibody display methods, including phage display methods (Van Berkel et al., paragraph 89). Thus, by teaching all the structural limitations of the “library of cells” as claimed, and a method with the specific methods steps as claimed, Van Berkel et al. anticipates the instant invention as claimed.
Claim Rejections - 35 USC § 103
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, 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 4-5 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2005/0170398 (2005), hereafter referred to as Van Berkel et al., in view of U.S. Patent Application Publication 2012/0101000 (2012), hereafter referred to as Zhou, with an effective filing date of 11/20/2009.
Van Berkel et al. teaches a host cell stably transformed with nucleic acid sequences encoding a single common light chain variable region and at least 2, including 3, 4 ,5 ,6 ,7 ,8 , 9, and 10 or more, different nucleic acids encoding different heavy chain variable region sequences, where the 2 or more heavy chain variable regions sequence have specificity for different target antigens, or different epitopes within the same target antigen, where the heavy chain variable regions are expressed and secreted as IgG, IgA, or IgM, and where the heavy chains are fully human or chimeric (Van Berkel et al., paragraphs 18-19, 55-63, 95, and 97). Van Berkel et al. further teaches that the at least two different heavy chain may be expressed at different levels (Van Berkel et al., paragraph 22, 62, and 83). Van Berkel et al. also teaches that host cell can be cloned and that the population of clones, i.e. a library of clones, can be screened for the production of a mixture of antibodies having a desired effect (Van Berkel et al., paragraph 22, 62, and 81). Van Berkel et al. teaches to transform the host cells with vector(s) encoding the 2 or more heavy chain variable regions, where each heavy chain is encoded by a different vector or by the same vector, and where each vector comprises a promoter and other regulatory elements for driving expression of the encoded variable regions (Van Berkel et al., paragraphs 63-66). Van Berkel et al. also teaches a particular expression vector for expression of the heavy chain where the vector comprises the HAVT20 leader sequence which comprises a secretion signal peptide (Van Berkel et al., paragraph 115). Van Berkel et al. further teaches that the host cells are eukaryotic cells, or mammalian cells such as human cells (Van Berkel et al., paragraph 68). In particular, Van Berkel et al. teaches the use of the immortalized PER.C6.TM cell as the host cell (Van Berkel al., paragraphs 68 and 70). In addition, Van Berkel et al. teaches that the nucleic acid molecules encoding the single common light chain and the two or more heavy chains are stably integrated into the chromosome of the host cell, where the integration employs site-specific integration into a predetermined position in the genome of the cell by homologous recombination (Van Berkel et al., paragraph 69, and 99). Van Berkel et al. teaches the selection of stable PER.C6.TM cells comprising the two heavy chain sequences and the common light chain sequence integrated into the genome, i.e. transgenic stable clones (Van Berkel et al., paragraph 119 and 126). Van Berkel et al. also teaches that the nucleic acid molecules encoding the two or more heavy chain variable regions and the single light chain variable region can be obtained from in vivo immunization methods, or from in vitro antibody display methods, including phage display methods (Van Berkel et al., paragraph 89).
While Van Berkel et al. teaches that various promoters can be used to express the heavy and light chain sequences in the host cell, and further teaches that heavy chains may be expressed at different levels, Van Berkel et al. does not specifically teach the use of at least two different regulatory elements to express the heavy chains. Zhou supplements Van Berkel et al. by teaching that different promoters can be used in the same or in separate vectors to express immunoglobulin chains in a mammalian cell, including a number of promoters taught by Van Berkel et al. (Zhou et al., paragraph 108). Thus, in view of the teachings of Zhou et al. that more than one immunoglobulin chain can be expressed in a mammalian cell using different promoters, and the teachings of Van Berkel al. that various promoters can be used to express the heavy and light chain sequences in the host cell and that the two or more heavy chains may be expressed at different levels, it would have been prima facie obvious to the skilled artisan at the time of filing to construct a single or multiple vectors encoding the two or more heavy chain variable regions and the common light chain variable region where each immunoglobulin chain is operably linked to its own promoter element and where the promoter element for each element is different, thus resulting in different levels of expression of each immunoglobulin chain in the library of cloned host cells taught by Van Berkel et al. with a reasonable expectation of success.
Claims 1-2, 7-10, 12, 16-19, 21, and 24-25 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2005/0170398 (2005), hereafter referred to as Van Berkel et al., in view of U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg '957, de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901, and the V-BASE sequence directory (1997) www2.mrc-lmb.cam.ac.uk.
Van Berkel et al. teaches a host cell stably transformed with nucleic acid sequences encoding a single common light chain variable region and at least 2, including 3, 4 ,5 ,6 ,7 ,8 , 9, and 10 or more, different nucleic acids encoding different heavy chain variable region sequences, where the 2 or more heavy chain variable regions sequence have specificity for different target antigens, or different epitopes within the same target antigen, where the heavy chain variable regions are expressed and secreted as IgG, IgA, or IgM, and where the heavy chains are fully human or chimeric (Van Berkel et al., paragraphs 18-19, 55-63, 95, and 97). Van Berkel et al. further teaches that the at least two different heavy chain may be expressed at different levels (Van Berkel et al., paragraph 22, 62, and 83). Van Berkel et al. also teaches that host cell can be cloned and that the population of clones, i.e. a library of clones, can be screened for the production of a mixture of antibodies having a desired effect (Van Berkel et al., paragraph 22, 62, and 81). Van Berkel et al. teaches to transform the host cells with vector(s) encoding the 2 or more heavy chain variable regions, where each heavy chain is encoded by a different vector or by the same vector, and where each vector comprises a promoter and other regulatory elements for driving expression of the encoded variable regions (Van Berkel et al., paragraphs 63-66). Van Berkel et al. also teaches a particular expression vector for expression of the heavy chain where the vector comprises the HAVT20 leader sequence which comprises a secretion signal peptide (Van Berkel et al., paragraph 115). Van Berkel et al. further teaches that the host cells are eukaryotic cells, or mammalian cells such as human cells (Van Berkel et al., paragraph 68). In particular, Van Berkel et al. teaches the use of the immortalized PER.C6.TM cell as the host cell (Van Berkel al., paragraphs 68 and 70). In addition, Van Berkel et al. teaches that the nucleic acid molecules encoding the single common light chain and the two or more heavy chains are stably integrated into the chromosome of the host cell, where the integration employs site-specific integration into a predetermined position in the genome of the cell by homologous recombination (Van Berkel et al., paragraph 69, and 99). Van Berkel et al. teaches the selection of stable PER.C6.TM cells comprising the two heavy chain sequences and the common light chain sequence integrated into the genome, i.e. transgenic stable clones (Van Berkel et al., paragraph 119 and 126). Van Berkel et al. also teaches that the nucleic acid molecules encoding the two or more heavy chain variable regions and the single light chain variable region can be obtained from in vivo immunization methods, or from in vitro antibody display methods, including phage display methods (Van Berkel et al., paragraph 89).
While Van Berkel et al. teaches that the source for the nucleic acids encoding the heavy chain variable regions and common light chain variable region can be obtained from in vivo immunization methods, Van Berkel et al. does not specifically teach to obtain the heavy chain nucleic acids from in vivo immunization of a transgenic mouse whose genome comprises a single rearranged human V-J gene operably linked to a constant region gene, where the mouse produces a population of B cells producing antigen-specific antibodies comprising the rearranged human light chain paired with a diversity of heavy chains. Lonberg et al. supplements Van Berkel et al. by teaching methods of obtaining an antibody comprising immunizing a transgenic mouse which expresses human variable region antibodies, collecting B cells from the immunized mice, making hybridomas from the B cells, obtaining DNA encoding human heavy and light chain variable regions and using DNA encoding the heavy and light chain variable regions to express human antibody in a host cell (Lonberg et al., paragraphs 179 and 332). Lonberg et al. teaches that a preferred embodiment is a transgenic mouse comprising a single rearranged light chain transgene and an unrearranged heavy chain transgene (Lonberg et al., paragraph 201). Lonberg et al. further teaches that the rearranged light chain is a kappa light chain (Lonberg et al. paragraphs 481-482). In particular, Lonberg et al. teaches that transgenic mice generated from a transgene construct comprising a single rearranged human light chain variable region can be bred with human heavy chain transgenic mice to produce a mouse which expresses a spectrum of antibodies in which the diversity of the primary repertoire is contributed by the unrearranged heavy chain transgene (Lonberg et al., paragraph 482). Lonberg et al. further teaches that, “The advantage of this scheme, as opposed to the use of unrearranged light chain miniloci, is the increased light chain allelic and isotypic exclusion that comes from having the light chain ready to pair with a heavy chain as soon as heavy chain VDJ joining occurs” (Lonberg et al., paragraph 482). Therefore, in view of the specific teachings of Van Berkel et al. to obtain 2 or more source DNA encoding rearranged human heavy chain variable regions and a single common rearranged human light chain variable region which pairs with each of the human heavy chain variable regions from an in vivo immunization method, it would have been prima facie obvious to the skilled artisan at the time of filing to obtain the source human heavy chain encoding DNA from the in vivo immunization method of mice disclosed by Lonberg et al. with a reasonable expectation of success.
While Lonberg et al. does not suggest any specific rearranged human light chain variable region, Lonberg et al. does teach the importance of generating antibody diversity in the disclosed transgenic mice. de Wildt et al. supplements Lonberg et al. by teaching that diversity is generated both by combinatorial rearrangement of different gene segments and the association of different heavy and light chains which generates a primary repertoire, and by somatic mutation and receptor editing which results in the secondary repertoire (de Wildt et a., page 895). Thus, in order to ensure added diversity in the repertoire due to somatic mutation and receptor editing, the skilled artisan at the time of filing would have been motivated to select a germline rearranged human light chain variable region sequence rather than a rearranged sequence that has already undergone somatic hypermutation as the primary repertoire is comprised of recombined germline sequences. Further, in regards to the selection of a human germline rearranged V-J variable region sequence, de Wildt et al., for example teaches that Vk 02/12 (also known as Vk1-39) and Vk 3-20 (also known as A27) are two of the most common human V gene segments found in the human antibody repertoire (de Wildt et al., page 896, Figure 1). De Wildt et al. further teaches that the germline sequence of human V region gene segments including the Vk1-39 and Vk3-20 gene segments and all five of the Vk gene segments was known at the time of filing, see for example the V-BASE Sequence Directory (de Wildt et al., page 897). Thus, based on the high frequency of usage of the Vk1-39 and VK3-20 variable region gene segment in the human antibody repertoire taught by de Wildt et al., and the disclosure of all the germline sequences of human Vk and Jk gene segments by the VBASE Directory, it would have been prima facie obvious to the skilled artisan to practice the methods of Van Berkel et al. in view of Lonberg et al. where the genome of the transgenic mouse comprises a rearranged human light chain V-K sequence comprises a rearranged human germline variable gene sequence such as a human germline IgkV1-39 gene segment sequence or a germline IgkV-320 gene segment sequence fused without mutation to any one of the five known human Jk gene segment sequences with a reasonable expectation of success of producing generating a diversity of B cells in the transgenic mouse in response to immunization which comprise antibodies useful as a source of heavy chain variable region sequences capable of functional pairing with the single/common rearranged transgenic light chain sequence.
Claims 4-5 and 13-14 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2005/0170398 (2005), hereafter referred to as Van Berkel et al., in view of U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg '957, de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901, and the V-BASE sequence directory (1997) www2.mrc-lmb.cam.ac.uk, as applied to claims 1-2, 7-10, 12, 16-19, 21, and 24-25 above, and further in view of U.S. Patent Application Publication 2012/0101000 (2012), hereafter referred to as Zhou, with an effective filing date of 11/20/2009.
Van Berkel et al. in view of Lonberg et al., de Wildt et al. and the V-BASE sequence directory provides the teachings and motivation to prepare a library of cloned host cells in which at least two different human heavy chain variable region encoding sequences and one common human light chain variable region encoding sequence are integrated into the genome of the cell, and where the heavy chain variable sequences and the common human light chain variable region coding sequence are derived from an immunized transgenic mouse whose genome comprises a single rearranged human V-J sequence comprising germline V sequence fused to germline J sequence without mutation, and unrearranged V-D-J sequences.
While Van Berkel et al. teaches that various promoters can be used to express the heavy and light chain sequences in the host cell, and further teaches that heavy chains may be expressed at different levels, Van Berkel et al. does not specifically teach the use of at least two different regulatory elements to express the heavy chains. Zhou supplements Van Berkel et al. by teaching that different promoters can be used in the same or in separate vectors to express immunoglobulin chains in a mammalian cell, including a number of promoters taught by Van Berkel et al. (Zhou et al., paragraph 108). Thus, in view of the teachings of Zhou et al. that more than one immunoglobulin chain can be expressed in a mammalian cell using different promoters, and the teachings of Van Berkel al. that various promoters can be used to express the heavy and light chain sequences in the host cell and that the two or more heavy chains may be expressed at different levels, it would have been prima facie obvious to the skilled artisan at the time of filing to construct a single vector or multiple vectors encoding the two or more heavy chain variable regions and the common light chain variable region where each immunoglobulin chain is operably linked to its own promoter element and where the promoter element for each element is different, thus resulting in different levels of expression of each immunoglobulin chain in the library of cloned host cells taught by Van Berkel et al. in view of Lonberg et al., de Wildt et al., and the V-BASE directory with a reasonable expectation of success.
Claims 22-23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2014/0314755 (2014), hereafter referred to as Logtenberg et al., in view of U.S. Patent Application Publication 2007/0059766 (2007), hereafter referred to as Logtenberg 2007.
Logtenberg et al. teaches methods of making a library of cells encoding rearranged heavy chain variable region sequences obtained from B cells of an immunized transgenic mouse whose genome comprises a transgene comprising a rearranged human V-K sequence which comprises a human immunoglobulin light chain germline V gene segment sequence fused to a human immunoglobulin light chain germline J gene segment without mutation, and where (Logtenberg et al., claims 31-41, paragraphs 92, and Table 12). Note that Table 12 give the sequence of germline human Vk gene segment sequence fused directly to a germline human Jk gene segment sequence with no mutation from the fusion. Logtenberg teaches to obtain nucleic acids encoding the heavy chain variable region from transgenic whose genome comprises the single rearranged human V-J sequence which have been immunized with an antigen and generating a bacterial cell phage display library where cells in the library comprise nucleic acid encoding the heavy chain variable region sequence and the single rearranged V-J variable region sequence present in the transgenic mouse (Logtenberg et al., paragraphs 196-197). Logtenberg et al. then teaches to screen and select for clones expressing an antibody which bind to the immunizing antigen, and to generate expression vectors comprising the sequence encoding the selected heavy chain sequences (Logtenberg et al., paragraphs 205-206). Logtenberg et al. further teaches to transfect mammalian cells, particularly PER.C6 cells, with at least two to five expression vectors encoding different selected heavy chain sequences and an expression vector encoding the single rearranged V-J light chain sequence, thus providing a library of such cells, and to select stable clones (Logtenberg et al., paragraphs 196, and 214).
Logtenberg et al. differs from the methods of instant claims 22-23 by not teaching to screen the cell library of stable cells comprising nucleic acids encoding at least two to five different selected heavy chain sequences and a single rearranged V-J light chain sequence, using a bioassay to measure either an antagonistic or activating activity of the expressed antibodies against a target molecule comprising the target epitope. Logtenberg 2007 supplements Logtenberg et al. by teaching methods of screening a library of cells for antagonistic or activating activity using a bioassay for antagonism or for activation of a target molecule comprising a target epitope comprising contacting a library of cells with different target epitopes and screening for and selecting a cell expressing binding proteins recognizing the target epitopes and having either an antagonistic or activating function based o the bioassay (Logtenberg 2007, paragraphs 19-21). Logtenberg 2007 further teaches where the library of cells comprises cells comprising at least two separate single polypeptide chain binding proteins having different target epitopes, and more specifically where the cells express at least two different antibodies (Logtenberg 2007, paragraphs 30-32). Logtenberg 2007, also teaches that the method comprises transferring the nucleic acids encoding at least two separate single antigen binding chains selected in the bioassay into a production cell (Logtenberg 2007, paragraph 19).
Therefore, in view of the motivation provided by Logtenberg 2007 to screen a library of cells expressing more than one antibody using a bioassay for antagonistic or activating activity in regards to a target molecule comprising a target epitope, it would have been prima facie obvious to the skilled artisan at the time of filing to practice the screening methods taught by Logtenberg 2007 using the library of cells taught by Logtenberg et al. with a reasonable expectation of success.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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).
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Claims1-2, 4-5, 7-10, 12-14, and 16-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,785,924, hereafter referred to as the ‘924 patent. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
This applicant has been identified by applicant as a divisional application of parent application 15/863,787, which issued as U.S. Patent No. 11,785,924. However, this application is not proper divisional application with respect to pending claims 1-2, 4-5, 7-10, 12-14, and 16-19 for the purposes of qualifying for prohibition of nonstatutory double patenting rejections under 35 U.S.C. 121. MPEP 804.01(A) states, “In order to obtain the benefit of 35 U.S.C. 121, claims must be formally entered, restricted in, and removed from an earlier application before they are filed in a divisional application . Geneva Pharms. Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373, 1379, 68 USPQ2d 1865, 1870 (Fed. Cir. 2003)”. In parent application 15/863,787, the applicant elected Group I, claims 1-20, which were drawn to methods of making a library of cells and a library of cells made therefrom comprising nucleic acids encoding two separate heavy chains having specificity for different targets or target epitopes. Instant claims 1-2, 4-5, 7-10, 12-14, and 16-19 correspond to the claims of Group I as set forth in the Restriction Requirement made in parent application 15/863,787. These claims were elected, examined, and not removed from the earlier application. As such, 35 U.S.C. 121 does not apply to instant claims 1-2, 4-5, 7-10, 12-14, and 16-19 with respect to the instant non-statutory double patenting rejection over the claims of the ‘924 patent.
Independent claims 1 and 11 of the ‘924 patent recite methods which are a species of instant method claim 1 in that the ‘924 patent claim methods recite the same method steps as recited in instant claim 1, but further limit the transgenic non-human animal to a transgenic murine animals comprise a transgene comprising a single human immunoglobulin light chain V gene segment fused to a single human immunoglobulin light chain J gene segment, wherein the fused V/J gene segments encode a rearranged immunoglobulin light chain variable region, wherein the transgene lacks a regulatory element that contributes to somatic hypermutation of the rearranged immunoglobulin light chain variable region, and wherein the transgene comprises a light chain constant region gene segment (‘924 claim 1), or a transgenic mice comprise a transgene comprising a single human immunoglobulin light chain V gene segment fused to a single human immunoglobulin light chain J gene segment, wherein the fused V/J gene segments encode a rearranged immunoglobulin light chain variable region, wherein the transgene lacks a regulatory element that contributes to somatic hypermutation of the rearranged immunoglobulin light chain variable region, and wherein the transgene is linked to an endogenous light chain constant region gene segment; wherein at least one of the endogenous light chain loci in said transgenic mice is functionally silenced (‘924 claim 11). The limitations in instant claims 2, 4-5, 7-9, 12-14, and 16-18 are recited dependent ‘924 patent claims 2-10 and 12-17. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann , 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Furthermore, the ‘924 method claims recite the generation of a library of cells with the exact same structural features as claimed in instant product claims 10 and 19. As such, the ‘924 method claims render obvious instant product claims 10 and 19.
Claims 1-2, 4-5, 7-10, 12-14, 16-19, 21, and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 22, 25-27, and 30-35 of copending Application No.15/866,374, hereafter referred to as the ‘374 application in view of U.S. Patent Application Publication 2005/0170398 (2005), hereafter referred to as Van Berkel et al.
The ’374 application claims recite methods which encompass the instant methods, the library of cells made using the method, and the composition of antibodies produced. The ‘374 application claims recite methods for producing a composition of antibodies or antigen-binding fragments thereof, the method comprising: providing transgenic murine animals comprising in their genome: a transgene comprising a single immunoglobulin light chain human V gene segment fused to a single immunoglobulin light chain human J gene segment, wherein the fused V/J gene segment encodes an immunoglobulin light chain variable region, wherein the transgene lacks a regulatory element that contributes to somatic hypermutation of the light chain variable region; wherein the transgene comprises a nucleic acid sequence encoding a light chain constant region gene segment and/or is linked to an endogenous light chain constant region gene segment; and wherein said transgenic murine animals produce populations of B cells producing antigen-specific antibodies, wherein said antibodies comprise the immunoglobulin light chain variable region encoded by the fused V/J gene segment paired with a diversity of heavy chain variable regions immunizing said transgenic murine animals to generate an immune response against antigens; isolating nucleic acid encoding heavy chain variable regions of antibodies produced by said transgenic murine animals; expressing nucleic acid sequences encoding at least two different heavy chain variable regions of antibodies produced by said transgenic murine animals and at least one light chain variable region encoded by the fused V/J gene segment, and pairing said at least one light chain variable region with said at least two different heavy chain variable regions in a cell; and harvesting antibodies or antigen-binding fragments thereof having binding specificities resulting from pairing of said light chain variable region with said at least two different heavy chain variable regions. While the ‘374 application claims do not further recite that one than one cell is produced using the method or that a “library” of cells is produced, it is noted that the methods of ‘374 encompass the production of more than one cell using the isolated nucleic acid encoding heavy chain variable regions of antibodies produced by said transgenic murine animals, which are not limited to the isolation of the at least tow different heavy chain variable regions transfected per cell. The specification of the ‘374 application has the same specification as the instant specification and thus supports the production of more than one “oligoclonic” cell. Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for obvious-type double patenting rejections. In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). In particular, the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). Thus, the methods of making a cell library and cell library obtained are disclosed obvious variants of the methods of the ‘374 application claims.
Furthermore, at the time of filing Van Berkel et al. supplements the ‘374 application by teaches a host cell stably transformed with nucleic acid sequences encoding a single common light chain variable region and at least 2, including 3, 4 ,5 ,6 ,7 ,8 , 9, and 10 or more, different nucleic acids encoding different heavy chain variable region sequences, where the 2 or more heavy chain variable regions sequence have specificity for different target antigens, or different epitopes within the same target antigen, where the heavy chain variable regions are expressed and secreted as IgG, IgA, or IgM, and where the heavy chains are fully human or chimeric (Van Berkel et al., paragraphs 18-19, 55-63, 95, and 97). Van Berkel et al. further teaches that the at least two different heavy chain may be expressed at different levels (Van Berkel et al., paragraph 22, 62, and 83). Van Berkel et al. also teaches that host cell can be cloned and that the population of clones, i.e. a library of clones, can be screened for the production of a mixture of antibodies having a desired effect (Van Berkel et al., paragraph 22, 62, and 81). Van Berkel et al. teaches to transform the host cells with vector(s) encoding the 2 or more heavy chain variable regions, where each heavy chain is encoded by a different vector or by the same vector, and where each vector comprises a promoter and other regulatory elements for driving expression of the encoded variable regions (Van Berkel et al., paragraphs 63-66). Van Berkel et al. also teaches a particular expression vector for expression of the heavy chain where the vector comprises the HAVT20 leader sequence which comprises a secretion signal peptide (Van Berkel et al., paragraph 115). Van Berkel et al. further teaches that the host cells are eukaryotic cells, or mammalian cells such as human cells (Van Berkel et al., paragraph 68). In particular, Van Berkel et al. teaches the use of the immortalized PER.C6.TM cell as the host cell (Van Berkel al., paragraphs 68 and 70). In addition, Van Berkel et al. teaches that the nucleic acid molecules encoding the single common light chain and the two or more heavy chains are stably integrated into the chromosome of the host cell, where the integration employs site-specific integration into a predetermined position in the genome of the cell by homologous recombination (Van Berkel et al., paragraph 69, and 99). Van Berkel et al. teaches the selection of stable PER.C6.TM cells comprising the two heavy chain sequences and the common light chain sequence integrated into the genome, i.e. transgenic stable clones (Van Berkel et al., paragraph 119 and 126). Thus, Van Berkel et al. provides motivation for making more than one cell with the structural features as claimed in order to allow for screening of the cell for selection of antibodies with desired characteristics. Van Berkel et al. also provide motivation for including various features within the expression vectors encoding the heavy chain variable regions such as choices of regulatory elements, secretion signals, and sequences for homologous recombination.
As such, in view of the motivation provided by Van Berkel et al. in regards to making more than one cell comprising at least two heavy chain sequences and a common light chain sequence, and the motivation provided by Van Berkel et al. to utilize various elements within expression vectors for expressing the at least two heavy chain sequences and the common light chin sequence, it would have been obvious at the time of filing to practice the methods of the ‘374 application to produce a library of cells with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634