DETAILED ACTION
Claims 28-47 are currently pending and under examination in the instant application. An action on the merits follows.
The present application is being examined under the pre-AIA first to invent provisions.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 9/23/24, 11/25/24, 1/17/25, 4/23/25, 12/5/25, and 4/28/26 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 an initialed and signed copies of the 1449s are attached to this action. Note that as the first IDS filed on 9/23/24, which cited over 300 references, was filed prior to the 1/19/25 effective date of 37 CFR 1.17(v), no sizing fee was required for this IDS or any subsequent IDS including the IDS filed on 4/23/25, 12/5/25, and 4/28/26 since the threshold of over 200 cited references was met prior to the effective date.
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 30-31 and 35-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
An amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972).
The preliminary amendment filed on 11/25/24 canceled all original claims and added new claims 28-47. New claims 30-31 and 35-36 recite a mouse ES cell whose genome comprises: 1) a nucleic acid encoding a human M-CSF polypeptide operably linked to promoter; 2) a nucleic acid encoding a human IL-3 polypeptide operably linked to a promoter; 3) a nucleic acid encoding a human GM-CSF polypeptide operably linked to a promoter; 4) a nucleic acid encoding a biologically active fragment of a full length human SIRPA polypeptide or a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide operably linked to a promoter; and 5) a nucleic acid encoding a human TPO polypeptide operably linked to a promoter, or a mouse embryo comprising said mouse ES cell. The limitation of 4) above, where the mouse ES cell comprises a nucleic acid encoding a biologically active fragment of a full length human SIRPA polypeptide or a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide operably linked to a promoter, is not described in the instant specification in such a way as to demonstrate that applicant had possession of the instant invention as claimed at the time of filing of the instant application, or as of the effective filing date of the instant application.
The specification is drawn to the generation of MITRG and MISTRG mice. In these, mice the endogenous genes for M-CSF, IL-3, TPO, and GM-CSF are replaced by their human counterparts, and a human SIRPa transgene has been randomly inserted into the mouse genome (specification, paragraph 107). It is further noted that specification discloses that the transgene comprises a human SIRPa gene encodes a full length SIRPa polypeptide. The specification does not disclose any nucleic acid encoding a biologically active fragment of human SIRPa, or any nucleic acid encoding any fusion protein of human SIRPa, particularly a SIRPa fusion protein comprising a biologically active fragment of human SIRPa The specification fails to provide any guidance for any biologically active fragment of human SIRPa, or any fusion protein comprising such a biologically active fragment of human SIRPa. At best, the specification in paragraph 48 provides a general definition of a “fragment” of a polypeptide, which is described as any subsequence of a larger polypeptide, and preferably at least about 50 amino acids up to about 2500 amino acids. In paragraph 56, the specification states that a polypeptide can be a "biologically active fragment"; however, the specification provides no description of any such biologically active fragments for any of the polypeptides disclosed in the specification including human SIRPa. The specification is silent as to any biologically active fragment of human SIRPa and further provides no description of any method of identifying or producing such as fragment. In addition to failing to adequately disclose a biologically active fragment of human SIRPa, the specification does not disclose a fusion protein comprising a biologically active fragment of human SIRPa. The only recitation of a "fusion" protein occurs in paragraph 56, which generally states that a polypeptide of the instant invention can include a fusion protein. No further disclosure or description of any fusion protein is provided in the instant specification. Importantly, there is no disclosure of a human SIRPa fusion protein comprising a biologically active fragment of human SIRPa. Thus, while the words “fusion protein” and “biologically active fragment” appear in the specification, the specification does not clearly or specifically provide a description of the subject matter currently claimed in the new claims such that it is clear that applicant was in possession of the invention as claimed at the time of filing. The applicant is reminded that “simply describing large genus of compounds is not sufficient to satisfy written description requirement as to particular species or sub-genus” Fujikawa v. Wattanasin, 39 USPQ2d 1895 (CA FC 1996). As such, the limitation in new claims 30 and 35 which recites that the nucleic acid encoding a biologically active fragment of a full-length human SIRPa polypeptide, and the limitation in new claims 31 and 36 which recites that the nucleic acid encodes a fusion protein comprising a biologically active fragment of a full length human SIRPA polypeptide, both appear to represent new matter not disclosed by the instant filed specification.
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 negated 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 28-29, 32-34, and 37-47 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2011/0200982 (August 18, 2011), hereafter referred to as Stevens et al., in view of Strowig et al. (2011) PNAS, Vol. 108(32), 13218-13223, which was printed on 8/11/11, but was published online on 7/25/11 (pnas.org PNAS 2011 108 (32) 13218-13223; published ahead of print July 25, 2011, doi:10.1073/pnas.1109769108), and U.S. Patent Application Publication 2012/0157667 (June 21, 2012), hereafter referred to as Chen et al.
Stevens et al. teaches genetically modified mice comprising one or more knock-in replacements of mouse cytokine gene(s) with their human counterparts (paragraphs 14-15, 31, 25-26, 66, 72, 75-76 78, and 121). Specifically, Stevens et al. teaches a genetically engineered mouse with a humanization of the mTPO, mGM-CSF, and mIL-3 genes whose genome comprises a replacement of the mouse TPO gene with a human TPO gene, a replacement of the mouse GM-CSF gene with a human GM-CSF gene, and a replacement of the mouse IL-3 gene with a human IL-3 gene, where each human gene sequence in the mouse genome is operably linked to a promoter (Stevens et al., paragraphs 14-15, 24-25, and 76-77). Stevens et al. further teaches to knock-in the human cytokine genes in mice with a Rag2 knockout mutation and the Il2rgIl2rg knockout mutation (Stevens et al., paragraphs 27, 72, and 75, and claims 1-8). Stevens et al. further teaches to engraft human hematopoietic stem cells in the Rag2/IL2rg knockout mice with human TPO, GM-CSF, and IL-3 knock-ins (Stevens et al., paragraphs 24-25 and 75-81). Stevens et al. teaches that the expression of the human cytokines TPO, GM-CSF, and IL-3 in the genetically modified mice dramatically improves reconstitution of specific human-blood lineage cells in the humanized mice (Stevens et al., paragraph 75-76, and 80-81). Stevens et al. further teaches methods of making said mice in which the genome of a mouse embryonic stem cell (ES cell), or a mouse ES cell which already comprises the Rag2/IL2rg knockout, is modified to comprise the replacement of the mouse TPO gene with a human TPO gene, a replacement of the mouse GM-CSF gene with a human GM-CSF gene, and a replacement of the mouse IL-3 gene with a human IL-3 gene, followed by introduction of the ES cell into an 8-cell mouse embryo which is then used to generate the transgenic mouse (Stevens et al., paragraphs 118-119, and 143).
Stevens et al. differs from the instant claimed mouse ES cells and embryos and methods of making said ES cells and embryos by not teaching that the mouse genome further includes a human M-CSF gene, or a human M-CSF gene and a human SIRPa gene. Strowig et al. supplements Stevens et al. by teaching a Rag2 -/- gc-/- (NSG) knockout mouse whose genome comprises a human SIRPa gene (hSIRPa-DKO)(Strowig et al., abstract and page 13218-13219). Strowig et al. further teaches that the introduction of the human SIRPa gene into the mouse genome occurs through introduction of the nucleotide sequence of the human SIRP into mouse ES cells (Strowig et al., pages 13218 and 13223). Strowig et al. further that human CD34+ hematopoietic stem cells exhibited enhanced engraftment in the hSIRPa-DKO mice (Strowig et al., page 13219). Strowig et al. further teaches to combine hSIRPa mice with additional human knockins to prolong human cell engraftment (Strowig et al., page 13222). In particular, Strowig et al. teaches the benefits of the human GM-CSF, IL-3, TPO knockin mice in improving the engraftment of human stem and progenitor cells, and in the development and maintenance of human macrophages and both HSC and HPC in the mouse (Strowig et al., page 13222). Thus, Strowig et al. provides motivation to further modify the human GM-CSF, IL-3, TPO knockin mice to express hSIRPa in order to improve human cell engraftment. Therefore, in view of the motivation provided by Strowig to modify the human GM-CSF, IL-3, TPO knockin mice to express hSIRPa in order to improve human cell engraftment, it would have been prima facie obvious to the skilled artisan at the time of filing to further modify the human GM-CSF/IL-3/TPO knockin mice, ES cells, and embryos taught by Stevens et al. to further include a human SIRPa gene as taught by Strowig et al. with a reasonable expectation of success in generating a genetically modified mouse expressing human GM-CSF, IL-3, TPO, and SIRPa which exhibits enhanced reconstitution of engrafted human hematopoietic cells.
Chen et al. further supplements Stevens et al. and Strowig et al. by teaching that expression of human M-CSF in mice improves reconstitution of human macrophages and monocytes in human hematopoietic stem cell engrafted mice (Chen et al., paragraphs 20, 32, 95, and 116). While Chen et al. introduced a plasmid vector encoding human M-CSF in the engrafted mice, both Stevens et al. and Strowig et al. provide motivation to introduce the human M-CSF gene as a knockin replacement of the mouse M-CSF gene. Stevens et al. teaches problems arising from the intravenous administration of cytokine vectors or their overexpression in transgenic animals can be overcome by the use of knockin technology (Stevens et al., paragraph 67). Strowig et al. as well teaches that transient approaches such as the injection of plasmid DNA can lead to overexpession which may have detrimental side effects due to the unphysiological expression of the cytokines (Strowig et al., page 13222). Therefore Strowig et al. recommends genetically engineering mice to replace the mouse gene with their human counterpart to order to express the cytokine in its appropriate niche at physiological levels (Strowig et al., page 13222). As such, in view of the motivation provided by Chen et al. to express M-CSF in mice to enhance engraftment of macrophages and monocytes, and the motivation provided by both Stevens et al. and Strowig et al. to genetically modify the genome of a mouse to replace a mouse cytokine gene with a human cytokine gene to avoid problems with unphysiological expression, it would have been prima facie obvious to the skilled artisan at the time of filing to further modify the human GM-CSF, IL-3, TPO, and SIRPa expressing mice, ES cells, and embryos taught by Stevens et al. and Strowig et al. to include a replacement of the mouse M-CSF gene with a human M-CSF gene with a reasonable expectation of success in generating mouse ES cells, mouse embryos, and ultimately a genetically modified mouse expressing human GM-CSF, IL-3, TPO, M-CSF and SIRPa which exhibits enhanced reconstitution of engrafted human hematopoietic cells.
Claims 31 and 36 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over U.S. Patent Application Publication 2011/0200982 (August 18, 2011), hereafter referred to as Stevens et al., in view of Strowig et al. (2011) PNAS, Vol. 108(32), 13218-13223, which was printed on 8/11/11, but was published ahead of print on 7/25/11 (pnas.org PNAS 2011 108 (32) 13218-13223; published ahead of print July 25, 2011, doi:10.1073/pnas.1109769108), and U.S. Patent Application Publication 2012/0157667 (June 21, 2012), hereafter referred to as Chen et al., as applied to claims 28-29, 32-34, and 37-47 above, and further in view of Lu et al. (2009) J. Biol. Chem., Vol. 284(19), 13233-13243.
As set forth in detail above, Stevens et al. in view of Strowig et al. and Chen et al. provide the teachings and motivation to make ES cells and embryos whose genome comprises a replacement of the endogenous GM-CSF, IL-3, TPO, and M-CSF genes with nucleic acid sequence encoding human GM-CSF, human IL-3, human TPO, and human M-CSF, and further comprises a nucleic acid encoding human SIRPa, where each human sequence is operably linked to a promoter.
While Stevens and Strowig et al. provide the motivation as set forth above to insert a human SIRPa gene in the genome of mouse ES comprising knockin of human GM-CSF, human IL-3, human TPO, and human M-CSF, Strowig et al. does not specifically teach to insert nucleic acid encoding a human SIRPa fusion protein. However, Lu et al. supplements Strowig et al. and Stevens et al. by teaching that insertion of a human gene into the mouse genome can include a sequence encoding an HA epitope at the 5' end of the human coding sequence in order to produce an HA epitope tagged human fusion protein which can be readily identified by commercial antibodies and which does not interfere with the function of the human protein (Lu et al., pages 13234, and 13235-13236, especially the bridging paragraph). Thus, based on motivation provided by Lu et al. to include a sequence encoding an HA epitope at the 5’ end of the coding sequence of a human gene in the genome of mouse cells, it would have been prima facie obvious to the skilled artisan at the time of filing to add a sequence encoding an HA epitope to the ‘5 end of the human SIRPa gene in order to express an HA epitope tagged human SIRPa fusion protein in the human SIRPa, human GM-CSF, human IL-3, human TPO, and human M-CSF mouse ES cells and embryos as taught by Stevens et al. in view of Strowig et al. and Chen 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).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 28-47 are rejected on the ground of nonstatutory double patenting as being unpatentable over 1) claims 1-15 of U.S. Patent No. 9,820,476, hereafter referred to as the ‘476 patent, OR 2) claims 1-12 of U.S. Patent No. 10,433,527, hereafter referred to as the ‘527 patent, OR 3) claims 1-17 of U.S. Patent No. 11,026,408, hereafter referred to as the ‘408 patent, each in view of U.S. Patent Application Publication 2011/0200982 (August 18, 2011), hereafter referred to as Stevens et al.
The ‘476 patent claims, the ‘527 patent claims, and the ‘408 patent claims, are all drawn to the same genetically modified, immunodeficient mouse whose genome comprises the same genetic modifications as recited in the genome of the mouse ES cells and embryos as claimed in the instant application. Claim 1 of the ‘476 patent, for example, recites a genetically modified mouse comprising in its genome a recombination activating gene 2 (Rag-2) gene knock-out, an IL2 receptor gamma chain (IL2rg) gene knock-out, a replacement of a mouse M-CSF gene with a nucleic acid encoding a human M-CSF polypeptide at a mouse M-CSF gene locus, a replacement of a mouse IL-3 gene with a nucleic acid encoding a human IL-3 polypeptide at a mouse IL-3 gene locus, a replacement of a mouse GM-CSF gene with a nucleic acid encoding a human GM-CSF polypeptide at a mouse GM-CSF gene locus, an insertion of a nucleic acid encoding a human SIRPA polypeptide, and a replacement of a mouse TPO gene with a nucleic acid encoding a human TPO polypeptide at a mouse TPO gene locus, wherein each of the nucleic acids encoding the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide is operably linked to a promoter, and wherein the mouse expresses the human M-CSF polypeptide, the human IL-3 polypeptide, the human GM-CSF polypeptide, the human SIRPA polypeptide, and the human TPO polypeptide. The exact same mouse is recited in the methods of the ‘527 and ‘408 patent claims. While the product claimed in these patents is mouse and not a mouse ES cell or mouse embryo, the mouse as claimed in the ‘476 claims, the ‘527 patent claims, and ‘408 patent claims encompass the claimed ES cells and embryos as the mouse may be a female mouse, and further a pregnant female mouse carrying an embryo which itself comprises embryonic stem cells. Thus, the instant claimed mouse ES cells, and mouse embryos are obvious variants of the instant claimed products.
In regards to the methods of making a mouse using the genetically modified mouse embryo as claimed in the instant claims, it is noted that the ‘476 patent claims are drawn to products comprising the mice, and methods of using the mice, and the ‘527 patent claims and the ‘408 patent claims are drawn to methods of using these mice. As such each of the ‘476 patent claims, the ‘527 patent claims, and ‘408 patent claims differ from the instant method claims which recite steps for using the genetically modified embryo to make the mouse by not reciting the specific steps by which the mice with the genotype specified have been made. However, methods of making transgenic mice with multiple gene modifications using genetically modified ES cells and embryos comprising said ES cells were known at the time of filing. Stevens et al. supplements the methods of the ‘476 patent OR the ‘527 patent OR the ‘408 patent by teaching methods of making similar multi-transgenic mice in which the genome of a mouse embryonic stem cell (ES cell), or a mouse ES cell which already comprises the Rag2/IL2rg knockout, is modified to comprise the replacement of the mouse TPO gene with a human TPO gene, a replacement of the mouse GM-CSF gene with a human GM-CSF gene, and a replacement of the mouse IL-3 gene with a human IL-3 gene, followed by introduction of the ES cell into an 8-cell mouse embryo which is then used to generate the transgenic mouse (Stevens et al., paragraphs 118-119, and 143).
Therefore, based on the transgenic mouse with the exact genomic structure claimed which is recited in the each of the ‘476 patent claims, the ‘527 patent claims, and the ‘408 patent claims, and the teachings of Stevens for methods of making multitransgenic mice by introducing the mutations into a mouse ES cell which is then introduced into a mouse embryo to generate the multitransgenic mouse, it would have been obvious to the skilled artisan to include methods steps for making the mice using mouse ES cells and mouse embryos in the methods recited in each of the ‘476 patent claims, the ‘527 patent claims, and the ‘408 patent claims with a reasonable expectation of success.
Additional Comments
Nonstatutory double patenting has not been applied between the instant claims and the claims of U.S. Patent No. 12,127,537 because the ‘537 patent claims are drawn to methods of breeding two different mice, neither of which comprise all of the genomic modifications as instantly claimed.
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.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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