DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/24/26 has been entered. Claims 38-42 are currently pending and under examination. An action on the merits follows.
The present application is being examined under the pre-AIA first to invent provisions. Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 103
The rejection of claims 38-40, and 42 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg '857, in view of WO 02/066,630 (2002), hereafter referred to as Murphy et al., de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901, Gellert et al. (2002) Ann. Rev. Biochem., Vol. 71, 101-132, Janeway and Wolpert, Immunobiology:The Immune System in Health and Disease, 5th edition. New York:Garland Science; 2001, pages 1-14, and Victor et al. (1994) J. Immunol., Vol. 152(7), 3467-3475, is maintained. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that the claims have been amended to recite that the transgenic non-human animal is for generating specific and high-affinity immunoglobulins and that the cited references, particularly Lonberg et al., do not teach this technical effect. The applicant argues that the rejection of record and stated claim interpretation ignore the technical effect achieved with the claimed transgenic animals. Applicant reiterates their previous argument that the art at the time of filing taught to use as many V and J gene segments as possible and that absent any data from an animal that deviates from that teachings, the skilled person would not have had a reasonable expectation that such transgenic animals would be useful for antibody generation. The applicant argues that Lonberg et al. did not provide any such data and that the skilled artisan would not have known whether the transgenic mice disclosed by Lonberg would have be capable of B cell development, antibody production, and antibody diversity. The applicant argues that Lonberg does not teach or suggest that a single transgenic mouse with common light chain is capable of pairing with multiple different heavy chains, and that many experiments would be needed to determine if a mouse as disclosed by Lonberg would be useful as a platform for antibody generation. In addition, the applicant argues that the commercial success and widespread licensing of the claimed transgenic non-human animal confirm that the claimed transgenic non-human animals are not obvious. The applicant argues that secondary consideration such as commercial success have been recognized by courts as evidence of non-obviousness. The applicant further states that they have provided evidence in the form of Exhibits A-F of the commercial success of the Memo® mouse and it licensing.
In response, it is first noted that 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). In addition, obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Lonberg et al. was cited for disclosing a number of different transgenes for insertion into the genome of a transgenic mouse. As set forth in the rejection of record, Lonberg et al. teaches that a preferred embodiment is a transgenic mouse comprising a 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 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). Thus, contrary to applicant’s argument, Lonberg et al. does indeed teach a transgenic mouse whose genome has an integrated transgene construct comprising a rearranged human light chain variable region sequence and further clearly teaches that after breeding this mouse with a human heavy chain transgenic mouse, such as the human heavy chain mouse taught by Lonberg which comprises multiple unrearranged human VH, DH, and JH gene segments, that the resulting mouse “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). Thus, Lonberg et al., one of skill in the art of transgenic mice for producing human/humanized antibodies, clearly expected that a mouse with a single rearranged (common) human light chain would be capable of associating with a number of rearranged human variable region heavy chains in a mouse to generate a diverse spectrum of antibodies. Furthermore, the fact that Lonberg themselves, both in the cited Lonberg publication, and in other of their own publications in the prior art, also made mice with both unrearranged light chains and unrearranged heavy chains, and taught ways to maximize the B cells and antibody output of these types of mouse, in no way teaches away from or invalidates the teachings of Lonberg for a different type of transgenic mouse which has a rearranged light chain instead of an unrearranged light chain transgene, and the teachings of Lonberg et al. that the mice with the rearranged human light chain V-J transgene have certain benefits over mice with an unrearranged human light chain V-J transgene. As taught by Lonberg, “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). Lonberg et al. thus clearly sees a benefit to using a rearranged light chain ready to pair with a heavy chain as soon as heavy chain VDJ joining occurs which is not predicated by increasing/maximizing antibody production or diversity.
In addition, in regards to applicant’s argument that Lonberg did not make a transgenic mouse with the single rearranged human VJ transgene and an unrearranged human heavy chain transgene, and show that the mouse produces a diversity of antibodies, or in particular produces antibodies that are specific and with high affinity following immunization with an antigen, the applicant is reminded that there is no requirement that the cited prior art have made or tested a disclosed compound, in this case a particular transgenic mouse, as a reference may enable one of skill in the art to make and use a compound even if the author or inventor did not actually make or reduce to practice that subject matter. Bristol-Myers, 246 F.3d at 1379; see also In re Donohue, 766 F.2d at 533. It is also reiterated that the transgenic non-human animal as claimed does not require any particular level of B cell production, antibody production, or antibody diversity. All that is required is that the animal produces antibodies comprising the human light chain variable region encoded by the transgene paired with a “diversity”, interpreted as more than one, immunoglobulin heavy chains resulting from somatic hypermutation which bind the target epitope. As applicant have noted in their previous responses, all the words of a claim should be considered and given weight. Applicant’s claims do not recite that the transgenic non-human animal exhibits “normal” B cell production or “normal” levels of antibody production, or a “normal” amount of antibody diversity. The claimed transgenic non-human animals, based on the current claim language, encompass animals with less than “normal” levels of B cells, antibodies, and/or antibody diversity. As for the ability of the mice disclosed by Lonberg et al. to generate an antibody with specificity and high affinity to an antigen, it is noted that applicant’s amendment has added an intended use to the preamble of the claimed product which is a transgenic non-human animal where the animal can be used to generate specific and high affinity antibodies. Lonberg et al. clearly teaches immunizing the various disclosed transgenic mice with antigen. Lonberg et al. et al. also teaches that the transgenic mice are for producing human sequence antibodies with high affinity to a specific antigen (Lonberg et al., abstract, paragraphs 23, 179, 217-218, and 232). In particular, note that Lonberg teaches that following exposure to antigen, B cells under somatic hypermutation and class switch and that these B cells or hybridomas obtained therefrom can be used to select antigen specific high affinity monoclonal antibodies (Lonberg et al., paragraph 329). Thus, Lonberg et al., as one of skill in the art, provides the teachings and a reasonable expectation of generating one or more specific high affinity antibodies from an immunized mouse comprising a single rearranged human light chain and an unrearranged human heavy chain transgene. Applicant has not provided any evidence which disputes this expectation.
Turning to applicant’s argument that the commercial success and widespread licensing of the claimed transgenic non-human animal, as evidenced by Exhibits A-F, confirm that the claimed transgenic non-human animals are not obvious, it is noted that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. MPEP 716.01(c). It is also noted that any evidence of secondary considerations must be commensurate in scope with the claimed invention. MPEP 716.02 (a) and (d). The applicant has not submitted an appropriate affidavit or declaration. Instead applicant has submitted Exhibits, referred to in their response as Exhibits A-F, but which have not actually been labeled as Exhibits A-F. These Exhibits are all press releases either from Merus itself, or from what appears to a market analyst. It is noted that the two Merus release dated 2025 and the analyst’s comments dated 2025 all involve either the clinical efficacy of a monoclonal antibody therapeutic referred to as Petosemtamab, or its market share as of 2025. None of these three releases reference transgenic non-human animal as claimed. The source of antibody is not disclosed and from at least one of the releases, Petosemtamab appears to be a bispecific antibody produced using a proprietary biclonics platform belonging to Merus. Thus, none of these press releases speak to the commercial success or licensing success of any transgenic non-human animal as claimed. Likewise, the Merus licensing agreement press release of 2021 refers to licensing of the proprietary Biclonics platform for producing bispecific antibodies and does not refer to transgenic non-human animal as claimed. The Merus press release from 2017 also discusses the Biclonics technology and not a transgenic non-human animal. Finally, the Merus press release from 2012 refers to a Memo® mouse for antibody production where the mouse is disclosed as having a single human light chain and a diversity of human heavy chains. There is no discussion of commercial sales or licensing of this mouse in this 2012 Press release. The applicant states in their response that this mouse, Memo® mouse, is also part of the BiClonics platform. However, none of the evidence provided actually teaches or illustrates the actual structure of the Memo® mouse such that it is unclear whether this mouse is actually encompassed by the claims as written, or disclosed in the instant specification. Further, as no structure is provided, and as the only mention in the one press release is for a mouse, it is noted that even if the Memo® mouse can be considered to be a species of the instant claims, this single mouse does not appear to be commensurate in scope with the claimed transgenic non-human animals. Thus, with the exception of the Merus 2012 release, which simply states that the Memo® mouse can be used to generate monoclonal antibodies for use in other platforms, all the other Exhibits are related to the therapeutic success or licensing of one particular therapeutic bispecific antibody, or the biclonics platform itself, neither of which is part of the invention as claimed. The applicant is reminded that evidence of commercial success of articles not covered by the claims subject to a 103 rejection is not probative of nonobviousness. See In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996). See also In re GPAC, 57 F.3d 1573, 1580, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); In re Paulsen, 30 F.3d 1475, 1482, 31 USPQ2d 1671, 1676 (Fed. Cir. 1994). Thus, for all the reasons cited above, applicant’s arguments regarding commercial success as a secondary consideration overcoming obviousness are not found persuasive.
Therefore, for the reasons set forth above, applicant’s arguments have not been found persuasive and the rejection of record stands.
The rejection of claim 41 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg '857, in view of WO 02/066,630 (2002), hereafter referred to as Murphy et al., and de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901, as applied to claims 38-40, and 42 above, and further in view of US Patent Application Publication 2006/0205077 (2006), hereafter referred to as Schwenk et al., is maintained. Applicant’s amendments and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail above.
The applicant has not argued this rejection separately from the rejection of claims 38-40, and 42. Applicant’s arguments concerning commercial success and the teachings of Lonberg et al. and de Wildt et al. have been addressed in detail above and have not been found persuasive. The applicant has not provided any additional arguments concerning the teachings of Schwenk et al. As such, the rejection of record stands.
Claim Rejections - 35 USC § 112
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 38-39, and 41-42 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 transgenic mouse comprising in its genome an integrated transgene comprising a single human immunoglobulin light chain non-mutated V gene segment and a single human immunoglobulin light chain non-mutated J gene segment, wherein the single human immunoglobulin light chain V gene segment and the single human immunoglobulin light chain J gene segment are joined to form a human V/J that encodes a human light chain variable region, does not reasonably provide enablement for making and using any species of transgenic non-human animals with the recited genomic modifications. 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 broadly on any non-human animal whose genome comprises an integrated transgene comprising a single human immunoglobulin light chain non-mutated V gene segment and a single human immunoglobulin light chain non-mutated J gene segment, wherein the single human immunoglobulin light chain V gene segment and the single human immunoglobulin light chain J gene segment are joined to form a human V/J that encodes a human light chain variable region, thus encompassing a genus of non-human transgenic non-human animals which include millions of species including insects, amphibians, invertebrates -both aquatic and land based, avians, fish, and mammals. The specification, however, while repeating the broad language regarding making and using a transgenic non-human animal, only provides specific guidance for generating transgenic mice and cells derived therefrom.
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). Munoz et al. also teaches in 2009, after the effective filing date of the instant application, that 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). Finally, Harding, published in 2013 which is 5 years after the effective filing date of the instant application, presents a review which concludes that the generation and use of ES cells from animals other mice, rats (as of 2013), and humans remains elusive because even though many attempts have been made to generate such cells, the cell lines described thus far for large mammals in particular do not meet the criteria for pluripotency (Harding et al. (2013) Stem Cell Research & Therapy, Vol. 4:23, pages 1-9, see page 30). 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.
In regards to making an using other types of non-human animal with the claimed genomic modification, the art at the time of filing teaches that 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 light chain equivalent variable region sequence or heterologous human light chain 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 animal as claimed.
Double Patenting
The provisional rejection of claims 38-42 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 22, 25, 27, and 31-35 of copending application 15/866,374, hereafter referred to as the ’374 application, is maintained. Applicant’s arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant states that as their arguments have overcome the grounds of rejection of the claims under 35 U.S.C. 103 that this provisional rejection should be withdrawn as it is the last remaining rejection. In response, the rejection of the claims under 35 U.S.C. 103 has not been overcome, see above, and the claims are further rejected under 35 U.S.C. 112, also see above. As such, the provisional rejection of claims 38-42 stands.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
Prosecution Insights