DETAILED CORRESPONDENCE
Claims 27-42 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 statement (IDS) submitted on 2/5/24 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner, and an initialed and signed copy of the 1449 is attached to this communication.
37 CFR 1.821-1.825
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), see for example pages 8-9 of the instant specification. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice To Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to this communication. Specifically, the specification lists numerous nucleotide and amino acids sequences, see for examples pages 65-68. While these sequences are followed by SEQ ID NOS, the applicant has not filed a sequence listing in both paper form and CRF as required. It is also noted that the specification on page 65 and page 66, and claims 30 and 33, refer to a SEQ ID NO:1 and a SEQ ID NO:11 for which no sequence is presented in the specification. Thus, the application as a whole fails to comply with 37 CFR 1.821-1.825. See also the attached Notice to Comply.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice To Comply with the response.
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) or 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 each of the prior-filed applications, 13/488,628, 13/412,936,13/093,156, 13/022,759, and provisional application 61/302,282, 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 instant claims recite the limitation that the genetically modified mouse comprises a human heavy chain variable region sequence encoding a human immunoglobulin heavy chain variable domain where the heavy chain variable domain sequence includes a VH3-49, VH3-66, VH4-28, or VH4-61 sequence. None of parent applications 13/488,628, 13/412,936,13/093,156, 13/022,759, and provisional application 61/302,282 disclose any one or all of these four specific VH sequences. These specific VH sequences were first disclosed in parent application 13/798,310. As such, benefit of priority to prior-filed applications 13/488,628, 13/412,936,13/093,156, 13/022,759, and provisional application 61/302,282 is denied.
Please note that the effective filing date of instant claims 39-42 is the filing date of parent application 13/798,310, which is 3/13/2013.
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 30 and 33 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 30 depends on claim 29 which depends on independent claim 1. Claim 29 recites that the human immunoglobulin kappa light chain variable region sequence is a Vkl-39/Jk5 sequence or a somatically hypermutated variant thereof. Claim 30 further limits the human Vk1-39/Jk5 kappa light chain variable sequence to a sequence which has a nucleotide sequence as set forth in nucleotides 2362 through 2686 of SEQ ID NO:1. Claim 33 depends on claim 32 which depends on independent claim 1. Claim 32 recites that the human immunoglobulin kappa light chain variable region sequence is a Vk3-20/Jk1 sequence or a somatically hypermutated variant thereof. Claim 33 further limits the human Vk3-20/Jk1 kappa light chain variable sequence to a sequence which has a nucleotide sequence as set forth in nucleotides 2373 through 2697 of SEQ ID NO:11. However, the specification does not provide the actual nucleotide sequence of either SEQ ID NOS:1 or 11, and further does not disclose a nucleotide sequence corresponding to nucleotides 2362 through 2686 of SEQ ID NO:1 or nucleotides 2373 through 2697 of SEQ ID NO:11. As noted above, the application further does not contain a sequence listing which defines the sequence of either SEQ ID NOS 1 or 11. As such, the metes and bounds of nucleotide sequence corresponding to nucleotides 2362 through 2686 of SEQ ID NO:1 or nucleotides 2373 through 2697 of SEQ ID NO:11 cannot be determined and the claims as a whole are indefinite.
In the interests of compact prosecution, claims 30 and 33 have been given their broadest reasonable interpretation of encompassing any nucleotide sequence comprising a rearranged sequence of human Vk1-39 and Jk5, which may or may not be somatically hypermutated (claim 30), or any nucleotide sequence comprising a rearranged sequence of human Vk3-20 and Jk1, which may or may not be somatically hypermutated.
Claims 37-38 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 37 recites a number of human Vh/D/Jh rearrangements which includes in part “439/1-26/3”. Claim 37 depends on claim 34 which provides the list of Vh gene sequences; however, the list of Vh in claim 34 does not include “439” as one of the Vh gene sequences. It is also noted that the specification does not list “439” as a human Vh gene segment sequence. As such, it is unclear whether “439” is a typographical error or a particular Vh gene sequence that may not be disclosed in the specification. It is noted the list in claim 34 does include Vh4-39. If “439” is a typo for “4-39”, it is suggested that applicant amend claim 37 to recite “4-39/1-26/3”. Claim 38 depends on claim 37 and thus is included in this rejection.
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 27-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-19 of U.S. Patent No. 10,143,186, hereafter referred to as the ‘186 patent, OR claims 1-25 of U.S. Patent No. 10,986,820, hereafter referred to as the ‘820 patent, in view of U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg et al.
The ’186 patent claims, see in particular claims 7 and 14, teach a method of using a genetically modified mouse to generate a variable region sequence for making an antibody, and a method of using a genetically modified mouse to make a common light chain antibody which while broader than the instant claimed methods of making a fully human antibody, encompasses the methods of the instant claims. In particular, note that ‘186 patent claim 14 recites the steps of identifying one or more human immunoglobulin heavy chain variable region sequence(s) from one or more B cells of a mouse, where the mouse expresses a single common rearranged light chain comprising human Vk1-39 or Vk3-20, and a repertoire or rearranged heavy chain sequences comprising human VH, DH, and JH sequences, and expressing one or more human heavy chain(s) comprising the identified human immunoglobulin heavy chain variable region sequence(s) in a mammalian cell that also expresses a human immunoglobulin light chain, which human immunoglobulin heavy chain(s) pair with the human immunoglobulin light chain to form the human common light chain antibody. In particular, note that the ‘186 patent claims recite a transgenic knock-in mouse whose genome comprises a single rearranged human light chain transgene comprising a human VK1-39 gene segment or VK3-20 gene segment and a human JK gene segment inserted into the mouse kappa light chain loci V and/or J region such that the mouse lacks endogenous VK and/or Jk gene segments, and more specifically a single rearranged human kappa light chain Vk39-1/Jk5 variable region sequence as set forth in nucleotides 2362 through 2686 of SEQ ID NO:1 or a single rearranged human kappa light chain Vk3-20/Jk1 sequences as set forth in nucleotides 2373 through 2697 of SEQ ID NO:11, and an unrearranged human heavy chain transgene comprising multiple human heavy chain V gene segments including at least the human VH 2-5, 3-23, 3-30, 3-33, 4-59, and 5-51 gene segments, all the human D gene segments, and all the human J gene segments inserted into the mouse heavy chain locus, and which produces chimeric human antibodies comprising human variable regions and mouse constant regions. The ‘820 patent claims recite similar methods for making an antibody that binds an antigen of interest comprising: immunizing a mouse with the antigen, where the mouse is a transgenic knock-in mouse whose genome comprises a single rearranged human light chain transgene comprising a human VK1-39 gene segment or VK3-20 gene segment and a human JK gene segment inserted into the mouse kappa light chain loci V and/or J region such that the mouse lacks endogenous VK and/or Jk gene segments, and more specifically a single rearranged human kappa light chain Vk39-1/Jk5 variable region sequence as set forth in nucleotides 2362 through 2686 of SEQ ID NO:1 or a single rearranged human kappa light chain Vk3-20/Jk1 sequences as set forth in nucleotides 2373 through 2697 of SEQ ID NO:11, and an unrearranged human heavy chain transgene comprising multiple human heavy chain V gene segments including at least the human VH 2-5, 3-23, 3-30, 3-33, 4-59, and 5-51 gene segments, all the human D gene segments, and all the human J gene segments inserted into the mouse heavy chain locus, and which produces chimeric human antibodies comprising human variable regions and mouse constant regions, determining an amino acid sequence of a human variable domain of the antibody that specifically binds the antigen of interest or determining a nucleotide sequence that encodes a human variable domain of the antibody that specifically binds the antigen of interest, and employing the amino acid sequence or the nucleotide sequence to produce an antibody that binds the antigen.
The ’186 patent claim methods OR the ‘820 patent claim methods differ from the instant methods by not teaching to further operably link the obtained heavy and light chain variable region nucleic acid sequences to human constant region sequences to produce fully human antibodies in cells. Lonberg et al. supplements the methods of the ’186 patent claims OR the ‘820 patent claims by teaching similar 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 to isolate the human variable region encoding sequences from a transgenic mouse which have been immunized with an antigen, where the sequences are isolated from a B cell or hybridoma derived from the B cell of the immunized mouse, and to splice the variable region sequences to desired human constant region sequences to produce sequence encoding a human antibody more suitable for human therapeutic uses where immunogenicity is preferably minimized (Lonberg et al., paragraphs 319-320 and 332). Lonberg et al. teaches that the polynucleotides having the resultant fully human encoding sequences can be expressed from an expression vector in a mammalian cell and purified for pharmaceutical formulation (Lonberg et al., paragraph 319-320 and 332). Thus, in view of the motivation and specific teachings of Lonberg et al. to use human variable region sequence from an antibody obtained from a transgenic mouse to generate fully human antibodies in cells by operably linking the human heavy and light chain variable sequences to human constant region sequences and expressing the sequences in host cells in order to generate antibodies which are more suitable for a human therapeutics, it would have been obvious to the skilled artisan at the time of filing to include the additional steps of operably linking the variable region sequences obtained in the methods of the ‘186 patent claims, OR the methods of the ‘820 patent claims to human constant region sequences, and to introduce those sequences into a cell to produce a fully human antibody with a reasonable expectation of success.
Claims 27-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,412,940, hereafter referred to as the ‘940 patent, OR claims 1-8 of U.S. Patent No. 11,026,407, hereafter referred to as the ‘407 patent, OR claims 7-12 of U.S. Patent No. 12,389,888, hereafter referred to as the ’888 patent, in view of U.S. Patent Application Publication 2006/0015957 (2006), hereafter referred to as Lonberg et al..
The claims of the ‘940 patent OR the ‘407 patent OR the ‘888 patent all recite methods of obtaining human heavy and light chain variable sequences from immunized transgenic mice where the transgenic mice exactly two unrearranged human immunoglobulin Vκ gene segments and five unrearranged human immunoglobulin Jκ gene segments operably linked to a mouse immunoglobulin light chain constant region sequence at the endogenous kappa light chain loci of the mouse, wherein the two unrearranged human immunoglobulin Vκ gene segments are a human Vκ1-39 gene segment and a human Vκ3-20 gene segment; and (ii) one or more unrearranged human immunoglobulin V.sub.H gene segments, one or more unrearranged human immunoglobulin D.sub.H gene segments, and one or more unrearranged human immunoglobulin J.sub.H gene segments operably linked to a mouse immunoglobulin heavy chain constant region sequence at the endogenous heavy chain loci of the mouse; wherein the unrearranged human immunoglobulin heavy chain and kappa light chain gene segments are capable of rearranging and encoding human immunoglobulin variable domains of an antibody, and wherein the mouse does not comprise endogenous immunoglobulin Vκ or Jκ gene segments that are capable of rearranging to form an immunoglobulin light chain variable region sequence. Note that the genetic structure of these mice only allow for the production of antibodies which have either a rearranged human VK1-39/J light chain sequence or a rearranged human VK3-20/J light chain sequence as the light chain variable region of the antibodies. It is further noted that the methods of the ‘888 patent further recite that the obtained variable region nucleotide sequences are used to make an antibody that binds to the antigen, and the methods of the ‘940 patent include methods of making fully human antibodies where the obtained variable region nucleotide sequences are operably linked to human constant region sequences to form fully human immunoglobulin heavy chain and fully human immunoglobulin light chains. Each of the methods of the ‘940, ‘407, and ‘888 patent claims is missing one or more step specifically recited in the instant claims.
Lonberg et al. supplements the methods of the ’940 patent claims OR the ‘407 patent claims OR the ‘888 patent claims by teaching methods to isolate the human variable region encoding sequences from a transgenic mouse comprising human light chain and heavy chain variable region gene segments which have been immunized with an antigen, where the sequences are isolated from a B cell or hybridoma derived from the B cell of the immunized mouse, and to splice the human variable region sequences to desired human constant region sequences to produce sequence encoding a human antibody more suitable for human therapeutic uses where immunogenicity is preferably minimized (Lonberg et al., paragraphs 319-320 and 332). Lonberg et al. teaches that the polynucleotides having the resultant fully human encoding sequences can be expressed from an expression vector in a mammalian cell and purified for pharmaceutical formulation (Lonberg et al., paragraph 319-320 and 332). Thus, in view of the motivation and specific teachings of Lonberg et al. to use human variable region sequence from an antibody obtained from a transgenic mouse to generate fully human antibodies in cells by operably linking the human heavy and light chain variable sequences to human constant region sequences and expressing the sequences in host cells in order to generate antibodies which are more suitable for a human therapeutics, it would have been obvious to the skilled artisan at the time of filing to include the additional steps of operably linking the variable region sequences obtained in the methods of the ‘940 patent claims, OR the methods of the ‘407 patent claims, OR the methods of the ‘888 patent claims, to human constant region sequences, and to introduce those sequences into a cell to produce a fully human antibody with a reasonable expectation of success.
Claims 27-42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,167,344, hereafter referred to as the ‘344 patent. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
The ‘344 patent claims recite similar methods of making a fully human antibody comprising expressing in a single cell: (a) a first nucleic acid sequence that encodes a first immunoglobulin heavy chain, the first nucleic acid sequence comprising a first human immunoglobulin heavy chain variable region sequence operably linked to a human immunoglobulin heavy chain constant region sequence, wherein the first human immunoglobulin heavy chain variable region sequence is identified from a B cell of a first mouse, and wherein the first mouse has been immunized with a first antigen of interest including a first epitope, and the first mouse comprises in its germline genome: (i) exactly two unrearranged human immunoglobulin Vκ gene segments and five unrearranged human immunoglobulin Jκ gene segments operably linked to a mouse immunoglobulin light chain constant region sequence at the endogenous kappa light chain loci of the mouse, wherein the two unrearranged human immunoglobulin Vκ gene segments are a human Vκ1-39 gene segment and a human Vκ3-20 gene segment; and (ii) one or more unrearranged human immunoglobulin V.sub.H gene segments, one or more unrearranged human immunoglobulin D.sub.H gene segments, and one or more unrearranged human immunoglobulin J.sub.H gene segments operably linked to a mouse immunoglobulin heavy chain constant region sequence at the endogenous heavy chain loci of the mouse; wherein the unrearranged human heavy chain and kappa light chain immunoglobulin gene segments of the first mouse are capable of rearranging and encoding human immunoglobulin variable domains of an antibody, wherein the first mouse does not comprise an endogenous immunoglobulin Vκ gene segment that is capable of rearranging to form an immunoglobulin light chain variable region sequence, and wherein the first human immunoglobulin heavy chain variable region sequence encodes a first human immunoglobulin heavy chain variable domain that recognizes the first epitope; and (b) a second nucleic acid sequence that encodes an immunoglobulin light chain, the second nucleic acid sequence comprising a human immunoglobulin kappa light chain variable region sequence fused with a human immunoglobulin light chain constant region sequence, wherein the human immunoglobulin kappa light chain variable region sequence comprises a human Vκ1-39 gene segment, a human Vκ3-20 gene segment, or a somatically hypermutated version thereof; maintaining the cell under conditions sufficient to express a fully human antibody; and isolating the antibody. The ‘344 methods are a species of the instant methods as they recite the same methods steps but are narrower in that they define the origin of the heavy and light chain sequences as being from a particular transgenic mouse. 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). As such, the ‘344 patent claim methods render obvious the instant methods of claims 27-42.
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 27-42 are rejected 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 et al., in view of WO 02/066,630 (2002), hereafter referred to as Murphy et al., Mendez et al. (1997) Nat. Genetics, Vol. 15, 146-156, and de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901.
The instant claims are drawn to a method of making a fully human antibody specific for an antigen by expressing in a cell a first nucleic sequence encoding a human heavy chain variable region sequence operatively linked to a human heavy chain constant region sequence and a second nucleic acid encoding a human kappa light chain variable region sequence operatively linked to a human light chain constant region sequence, where the human kappa light chain variable region sequence comprises a rearranged human Vk1-39/J sequence or a human Vk3-20/J sequence, or a somatically hypermutated variant thereof, an where the human heavy and light chain variable regions encoded by the variable region sequences together recognize the antigen.
Lonberg et al. teaches transgenic mice with disrupted endogenous immunoglobulin loci whose genome comprises human unrearranged or rearranged human immunoglobulin heavy and light chain transcripts useful for producing human or humanized antibodies (Lonberg et al., paragraphs 16-17, 25, Figure 33, 196-197, 201, 222, 232-233, and 265). Lonberg et al. further teaches transgenic mice comprising unrearranged human light chain transgenes which express chimeric immunoglobulin light chains comprising a human variable region and a mouse constant region (Lonberg et al., claims 10-20). 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). Lonberg et al. further teaches to isolate the human variable region encoding sequences from a transgenic mouse which have been immunized with an antigen, where the sequences are isolated from a B cell or hybridoma derived from the B cell of the immunized mouse, and to splice the variable region sequences to desired human constant region sequences to produce sequence encoding a human antibody more suitable for human therapeutic uses where immunogenicity is preferably minimized (Lonberg et al., paragraphs 319-320 and 332). Lonberg et al. then teaches to express the fully human encoding sequences from an expression vector in a host cell, such as a mammalian cell, and to purify the antibody for pharmaceutical formulation (Lonberg et al., paragraphs 319-320 and 332).
In regards to the unrearranged heavy chain, Lonberg et al. further teaches that the unrearranged human heavy chain transgene comprises several human VH, DH, and JH gene segments (see for example Lonberg et al., Figure 25 for the pHC2 transgene). Lonberg et al. also teaches to disrupt one or both of the endogenous mouse light chain or heavy chain regions by disrupting the J region, which results in functional silencing of these loci (Lonberg et al., paragraphs 17, 35, 37,296, and 298). Lonberg et al. also teaches that the transgene comprises a kappa or lambda light chain promoter, either human or mouse, and other regulatory sequences such as a mouse kappa light chain intronic enhancer, a mouse 3' kappa enhancer, and the combination of an intronic enhancer with a 3' enhancer (Lonberg et al., paragraphs 200, 227, 252, 266, 473, 480, and 706).
While Lonberg et al. clearly teaches transgenic mice comprising unrearranged human light chain transgenes which express chimeric immunoglobulin light chains comprising a human variable region and a mouse constant region, Lonberg et al. does not specifically teach a transgenic mouse comprising a rearranged human light chain transgene which expresses chimeric immunoglobulin light chains comprising a human variable region and a mouse constant region. However, as discussed in detail above, Lonberg et al. does specifically teach that transgenic mice expressing human light chain variable regions can be made using either an unrearranged or rearranged human immunoglobulin light chain transgene. Lonberg et al. further provides specific motivation for using a rearranged rather than an unrearranged light chain transgene by teaching that the advantage of using a rearranged light chain transgene, 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). Furthermore, at the time of filing, Murphy et al. teaches that mice producing fully human antibodies have reduced affinity to mouse receptors which affects B cell maturation and survival and that this can be avoided by producing mice which express chimeric antibodies comprising human variable regions and mouse constant regions (Murphy et al., pages 42-43). According to Murphy et al., the mouse Fc regions in the chimeric antibodies are more specific than human Fc regions in their interactions with Fc receptors and other receptors important for strong and specific immune response, proliferation and maturation of B cells, and affinity maturation of antibodies (Murphy et al., pages 43-44). Murphy et al. further supplements Lonberg et al. by teaching “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for homologous or orthologous human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). Thus, the transgenic mice taught by Murphy et al. comprise the kappa intronic enhancer and 3’ enhancer. In addition, Murphy et al. teaches that immunization of these transgenic mouse generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further teaches that the human immunoglobulin knock-in mice can be used in methods of making antibodies comprising immunizing the transgenic knock-in mice with an antigen, isolating heavy and light chain nucleic acids encoding the variables regions of the antibody, operably linking them to human constant region gene sequences, inserting the sequences into cells, expressing the fully human antibodies in the cells, and recovering the antibodies (Murphy et al., page 52). Mendez et al. further supplements Lonberg et al. and Murphy et al. by teaching a YAC comprising the human heavy chain V gene segments 1-2, 1-8, 1-18, 1-24, 2-5, 3-7, 3-9, 3-11, 3-13, 3-15, 3-20, 3-23, 3-30, 3-33, 3-48, 3-49, 3-66, 4-28, 4-31, 4-39, 4-59, 4-61, 5-51, and 6-1, all of the human heavy chain D gene segments, which includes D1-7, D1-26, D3-3, D3-10, D3-16, D3-22, D5-5, D5-12, D6-6, D6-13, and D7-27, and all of the human heavy chain J gene segments (J1-J5) which can be successfully inserted into a mouse genome and undergo productive rearrangement (Mendez et al., Figure 1a and page 148).
Thus, based on the motivation provided by Lonberg et al. to make a transgenic mouse whose genome comprises a human immunoglobulin light chain transgene and which expresses a chimeric immunoglobulin light chain comprising a human light chain variable region and a mouse light chain constant region, the motivation provided by Lonberg et al. to use a rearranged human immunoglobulin light chain transgene over an unrearranged light chain transgene, the detailed guidance provided by Lonberg et al. for making immunoglobulin light chain transgenes comprising a rearranged human light chain variable region, the motivation to use mouse constant region genes over human constant region genes in transgenic mice taught by Murphy et al. and the teachings of Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences and all or part of the endogenous mouse heavy chain V/D/J region with human VDJ sequences, and the teachings of Mendez et al. for transgenic mice whose genome comprises an unrearranged human heavy chain transgene with all the V, D, and J gene segments listed above and which expresses human heavy chains, it would have been prima facie obvious to the skilled artisan at the time of filing to make a transgenic mouse whose endogenous kappa light chain locus comprises a human rearranged kappa light chain variable region sequence operably linked to the endogenous mouse kappa light chain constant region sequence and whose endogenous heavy chain locus comprises a plurality of unrearranged human V, D, and J gene segments operably linked to an endogenous mouse heavy chain constant region gene segments, and which expresses a chimeric light chain comprising a human variable region and a mouse constant region, and to 1) immunize these mice according to Lonberg et al. and Murphy et al., 2) obtain human kappa light chain and human heavy chain variable sequences from B cells isolated from the immunized mice, 3) operatively link both the heavy and light chain variable sequences to human constant region sequence, and 4) express the sequences within a mammalian host cell to produce a fully human antigen specific antibody 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, it would have been prima facie obvious to the skilled artisan at the time of filing to select a germline rearranged human light chain variable region sequence rather than a rearranged sequence that has already undergone somatic hypermutation in response to a specific antigen. In regards to the selection of a human germline rearranged V-J variable region sequence comprising IgKV1-39 or Vk3-20, de Wildt et al. teaches that Vk 02/12 (also known as Vk1-39) and VK3-20 (also known as A27) are two of the most common human V gene segments found in the human antibody repertoire and are capable of pairing with a large number of different heavy chain variable regions (de Wildt et al., page 896, Figure 1). In particular, de Wildt et al. teaches where the heavy chains found to frequently pair with both Vk-19 and Vk3-20 include VH3-23, VH5-51, VH3-30, VH4-39, and VH4-59 (de Wildt et al., page 459). De Wildt et al. further teaches that the germline sequence of human V region gene segments including Vk1-39 and Vk3-20 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 human Vk1-39 variable region gene segment and the human VK3-20 variable region gene segment in the human antibody repertoire taught by de Wildt et al., the common association of human light chains comprising Vk1-39 or Vk3-20 sequence and human heavy chains comprising a VH sequence such as VH3-23, VH5-51, VH3-30, VH4-39, or VH4-59, and the teachings and motivation provided by Murphy et al. and Mendez et al. to include in the modified heavy chain locus of all of these aforementioned human VH gene segments, all of the human D gene segments, and all of the human J gene segments, it would have been prima facie obvious to the skilled artisan at the time of filing to both make a transgenic mouse according to the teachings of Lonberg et al., in view of Murphy et al., Mendez et al., and de Wildt et al. where the rearranged germline human light chain variable gene sequence comprises a germline IgkV1-39 gene segment or a germline IgkV3-20 gene segment, and the human unrearranged heavy chain variable gene sequences comprise the human heavy chain V gene segments 1-2, 1-8, 1-18, 1-24, 2-5, 3-7, 3-9, 3-11, 3-13, 3-15, 3-20, 3-23, 3-30, 3-33, 3-48, 3-49, 3-66, 4-28, 4-31, 4-39, 4-59, 4-61, 5-51, and 6-1, all of the human heavy chain D gene segments, which includes D1-7, D1-26, D3-3, D3-10, D3-16, D3-22, D5-5, D5-12, D6-6, D6-13, and D7-27, and all of the human heavy chain J gene segments (J1-J5) and wherein the mouse in response to antigen produces a repertoire of antibodies where the light chains of the antibodies comprise human Vk1-39 or Vk3-20 sequence and the associated heavy chains comprise a heavy chain VH sequence comprising at least one of human VH3-23, VH5-51, VH3-30, VH4-39, or VH4-59, in combination with a D and J gene segment including those combinations listed in instant claims 37 and 38 with a reasonable expectation of success, and to 1) immunize these mice according to Lonberg et al. and Murphy et al., 2) obtain human kappa light chain and human heavy chain variable sequences from B cells isolated from the immunized mice, 3) operatively link both the heavy and light chain variable sequences to human constant region sequence, and 4) express the sequences within a mammalian host cell to produce a fully human antigen specific antibody with a reasonable expectation of success.
Finally, in regards to the specific combination of VK1-39 and JK5, or VK3-20 and JK1 , as noted above de Wildt et al. teaches that the sequences for all the human Ig kappa gene sequences were available at the time of filing in the V-BASE Sequence Directory, these sequences include the VK and JK gene sequences. As such, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize any of the five well-known human JK gene segments, including JK5 or JK1, in a rearranged V kappa transgene comprising VK 1-39 or VK 3-20 as taught by Lonberg et al. in view of Murphy, Mendez, and de Wildt et al., as the use of any 1 of the 5 human JK gene segments with VK1-39 or VK3-20 would be predicted to function equally well in producing a light chain in a transgenic mouse with a reasonable expectation of success.
Claims 27-30, 34-36, and 39-42 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2010/0146647 (June 10, 2010), hereafter referred to as Logtenberg et al., with an effective filing date of 6/27/2008, in view of WO 02/066,630 (2002), hereafter referred to as Murphy et al., and Mendez et al. (1997) Nat. Genetics, Vol. 15, 146-156.
Logtenberg et al. teaches a transgenic mouse in which a single rearranged immunoglobulin light chain variable region sequence (VL) comprising germline sequence is inserted into an endogenous mouse locus (Logtenberg et al., paragraphs 23-34, 59, 61, 65, and 72). In one embodiment, Logtenberg et al. teaches that the insertion of sequence comprising a rearranged germline human VL region sequence, a mouse kappa intron enhancer sequence, and a mouse or rat constant region sequence (Logtenberg et al., paragraphs 27-28, and 65). Logtenberg et al. teaches a specific embodiment where the human variable region gene present in the rearranged VL is VK1-39 (also referred to as O12) (Logtenberg et al., paragraphs 25 and 37). Logtenberg et al. further teaches to insert the rearranged human VL region into the endogenous mouse light chain kappa or lambda locus so as to functionally inactive the endogenous locus in mice containing the rearranged human VL (Logtenberg et al., paragraph 61). Logtenberg et al. also teaches that a light chain comprising the selected rearranged VL region is capable of pairing with multiple rearranged heavy chains (Logtenberg et al., paragraphs 23 and 73). Logtenberg et al. further teaches crossing the transgenic mouse which comprises the rearranged human VL region with a transgenic mouse known in the art whose genome comprises a non-rearranged human H chain immunoglobulin loci (Logtenberg et al., paragraphs 64 and 194-195). Finally, Logtenberg et al. teaches methods of immunizing a transgenic mouse comprising a rearranged human kappa light chain and a human VH locus with an antigen (Logtenberg et al., paragraphs 43-44, 66, 73, and 194-215).
Logtenberg et al. differs from the instant invention as claimed by not teaching to insert the rearranged human VL into the endogenous mouse kappa light chain locus such that the resulting mouse does not comprise functional unrearranged Vk and/or Jk gene segments. Logtenberg et al. further does not specifically teach which heavy chain V, D, and J genes segments which contribute to heavy chains which pair with the single rearranged light chain, or teach that the single rearranged light chain Vk/Jk segment is Vk 1-39/Jk-5. Logtenberg et al. also does not each to further isolate a cognate pair of light and heavy chain variable regions from the immunized mice, to operatively link the obtained heavy and light chain variable region sequence with human constant region sequence, and to express a fully human antibody in a host cell.
Murphy et al. supplements Logtenberg et al. by teaching “knock-in” transgenic mice in which all or part of the endogenous genomic immunoglobulin light chain variable region and/or heavy chain variable region are substituted by homologous recombination for homologous or orthologous human light chain and/or heavy chain genes respectively (Murphy et al., paragraphs 35-36, 38-44, 46-48, 83, 85, 99, and claims 1-4, and 7-10). Murphy et al. further teaches that direct substitution of the mouse light and heavy chain VJ/VDJ regions with human VJ/VDJ regions such that all the sequences necessary for proper transcription, recombination, and/or class switching in the mouse genome remain intact (Murphy et al., paragraph 85). Thus, the transgenic mice taught by Murphy et al. comprise the kappa intronic enhancer and 3’ enhancer. In addition, Murphy et al. teaches that immunization of these transgenic mouse generates antibodies comprising human variable regions and mouse constant regions (Murphy et al., paragraphs 46 and 49). In regards to the light chain, Murphy et al. teaches “knock-in” of the human kappa light chain and/or lambda light chain into the endogenous mouse kappa or lambda light chain variable region respectively (Murphy et al., paragraph 99). Murphy et al. further teaches that the human immunoglobulin knock-in mice can be used in methods of making antibodies comprising immunizing the transgenic knock-in mice with an antigen, isolating antigen specific antibodies, isolating heavy and light chain nucleic acids encoding the variables regions of the antibody, operably linking them to human constant region gene sequences, inserting the sequences into cells, expressing the fully human antibodies in the cells, and recovering the antibodies (Murphy et al., page 52). Mendez et al. further supplements Logtenberg et al. and Murphy et al. by teaching a YAC comprising the human heavy chain V gene segments 1-2, 1-8, 1-24, 2-5, 3-7, 3-9, 3-11, 3-13, 3-15, 3-20, 3-23, 3-30, 3-33, 3-48, 4-31, 4-39, 4-59, 5-51, and 6-1, all of the human heavy chain D gene segments, which includes D1-7, D1-26, D3-3, D3-10, D3-16, D3-22, D5-5, D5-12, D6-6, D6-13, and D7-27, and all of the human heavy chain J gene segments which can be successfully inserted into a mouse genome and undergo productive rearrangement (Mendez et al., Figure 1a and page 148). Thus, in view of the teachings of Logtenberg et al. to cross the transgenic mouse which comprises the rearranged human VL region with a transgenic mouse known in the art whose genome comprises a non-rearranged human H chain immunoglobulin loci and to further insert the rearranged human VL region into the endogenous mouse light chain kappa or lambda locus, the teachings of Murphy et al. to replace all or part of the endogenous mouse light chain V/J region with human VJ sequences, and the teachings of Mendez et al. for transgenic mice whose genome comprises an unrearranged human heavy chain transgene with all the V, D, and J gene segments listed above and which expresses human heavy chains, it would have been prima facie obvious to the skilled artisan at the time of filing to make a transgenic mouse according to Logtenberg et al. wherein the rearranged Vk1-39/J sequence replaces all the endogenous mouse light chain VK and/or JK sequences and whose genome further comprises the human heavy chain transgene taught by Mendez et al. with a reasonable expectation of success, and to 1) immunize these mice according to Logtenberg et al. and Murphy et al., 2) obtain human kappa light chain and human heavy chain variable sequences from B cells isolated from the immunized mice, 3) operatively link both the heavy and light chain variable sequences to human constant region sequence, and 4) express the sequences within a mammalian host cell to produce a fully human antigen specific antibody with a reasonable expectation of success.
Furthermore, in regards to the specific combination of VK1-39 and JK5, while Logtenberg et al. exemplifies the combination of VK1-39 and JK1, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize any of the five well-known human JK gene segments, including JK5, in a rearranged V kappa transgene comprising VK 1-39 as taught by Logtenberg et al. as the use of any 1 of the 5 human JK gene segments would be predicted to function equally well in producing a light chain in a transgenic mouse with a reasonable expectation of success.
Claims 31-33 and 37-38 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over US Patent Application Publication 2010/0146647 (June 10, 2010), hereafter referred to as Logtenberg et al., in view of WO 02/066,630 (2002), hereafter referred to as Murphy et al., and Mendez et al. (1997) Nat. Genetics, Vol. 15, 146-156, as applied to claims 27-30, 34-36, and 39-42 above, and further in view of US Patent Application Publication 2008/0069822 (March 20, 2008), hereafter referred to as Jensen et al., and de Wildt et al. (1999) J. Mol. Biol., Vol. 285, 895-901.
The teachings and motivation provided by Logtenberg et al., Murphy et al. and Mendez et al. for making a transgenic mouse in which a single rearranged immunoglobulin kappa light chain Vk1-39/J segment and an unrearranged human heavy chain locus are inserted into the germline of the mouse, and using the mouse to obtain fully human antibodies by 1) immunizing the mouse with antigen, 2) obtaining human kappa light chain and human heavy chain variable sequences from B cells isolated from the immunized mice, 3) operatively linking both the heavy and light chain variable sequences to human constant region sequence, and 4) expressing the sequences within a mammalian host cell to produce a fully human antigen specific antibody with a reasonable expectation of success, have been set forth in detail above.
While Logtenberg et al. generally teaches to insert a rearranged kappa light chain V-J segment into the mouse’s genome, and specifically teaches germline sequence IGKV1-39/JK1 as a preferred embodiment, Logtenberg et al. does not specifically teach to insert a rearranged IGKV3-20 germline sequence. Logtenberg et al. further does not teach specific combinations of heavy chain V, D, J gene segment which when recombined produce a heavy chain variable region sequence which can functionally associate with the rearranged Vk1-39/J variable region sequence. However, Logtenberg et al. does teach that the rationale for selecting IGKV1-39 was that human IGKV1-39 is a frequently observed in the human repertoire (Logtenberg et al., paragraph 25). Jensen et al. supplements Logtenberg et al. by teaching that while IGKV1-39 is among the most frequently used light chain V genes in the human immunoglobulin repertoire, IGKV3-20 is in fact the most frequently expressed light chain gene in humans (Jensen et al., paragraph 179). As such, since Logtenberg et al. teaches to select human Vk genes which are frequently observed in the human repertoire, and Jensen et al. teaches that IGVK3-20 is the most frequently expressed light chain gene in humans, it would have been prima facie obvious to the skilled artisan at the time of filing to substitute IGK3-20 for IGK1-39 in the rearranged human V-J segment in the transgenic mice and methods as taught by Logtenberg et al. in view of Murphy et al. and Mendez et al. with a reasonable expectation of success. Further, based on the teachings of Logtenberg that the Jk1 gene segment can be used, it would have been further prima facie obvious to the skilled artisan at the time of filing to use a rearranged IGK3-20/JK1 segment encoding a germline VL domain in the transgenic mice taught by Logtenberg et al. in view of Murphy et al. and Mendez et al. with a reasonable expectation of success. Alternatively, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize any of the five well-known human JK gene segments, including JK5, in a rearranged V kappa transgene comprising VK 3-20 as taught by Logtenberg et al. in view of Jensen et al. as the use of any 1 of the 5 human JK gene segments would be predicted to function equally well in producing a light chain in a transgenic mouse with a reasonable expectation of success.
Furthermore, in regards to the functional combinations of a light chain comprising the rearranged human Vk1-39 light chain or Vk3-20 light chain and a human heavy chain as set forth in claims 37-38, it is noted that De Wildt et al. further supplements Logtenberg et al., Murphy et al., and Mendez et al. by teaching that Vk 02/12 (also known as Vk1-39) and VK3-20 (also known as A27) are two of the most common human V gene segments found in the human antibody repertoire and are capable of pairing with a large number of different heavy chain variable regions (de Wildt et al., page 896, Figure 1). In particular, de Wildt et al. teaches where the heavy chains found to frequently pair with both Vk-19 and Vk3-20 include VH3-23, VH5-51, VH3-30, VH4-39, and VH4-59 (de Wildt et al., page 459). De Wildt et al. further teaches that the germline sequence of human V region gene segments, both light and heavy chain, including Vk1-39 and Vk3-20, were 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 human Vk1-39 variable region gene segment and the human VK3-20 variable region gene segment in the human antibody repertoire taught by de Wildt et al., the common association of human light chains comprising Vk1-39 or Vk3-20 sequence and human heavy chains comprising a VH sequence such as VH3-23, VH5-51, VH3-30, VH4-39, or VH4-59, and the teachings and motivation provided by Murphy et al. and Mendez et al. to include in the modified heavy chain locus of all of these aforementioned human VH gene segments, all of the human D gene segments, and all of the human J gene segments, it would have been prima facie obvious to the skilled artisan at the time of filing to both make a transgenic mouse according to the teachings of Logtenberg et al., in view of Murphy et al., Mendez et al., and de Wildt et al. where the rearranged germline human light chain variable gene sequence comprises a germline IgkV1-39 gene segment or a germline IgkV3-20 gene segment, and the human unrearranged heavy chain variable gene sequences comprise the human heavy chain V gene segments 1-2, 1-8, 1-18, 1-24, 2-5, 3-7, 3-9, 3-11, 3-13, 3-15, 3-20, 3-23, 3-30, 3-33, 3-48, 3-49, 3-66, 4-28, 4-31, 4-39, 4-59, 4-61, 5-51, and 6-1, all of the human heavy chain D gene segments, which includes D1-7, D1-26, D3-3, D3-10, D3-16, D3-22, D5-5, D5-12, D6-6, D6-13, and D7-27, and all of the human heavy chain J gene segments (J1-J5), and wherein the mouse in response to antigen produces a repertoire of antibodies where the light chains of the antibodies comprise human Vk1-39 or Vk3-20 sequence and the associated heavy chains comprise a heavy chain VH sequence comprising at least one of human VH3-23, VH5-51, VH3-30, VH4-39, or VH4-59, in combination with a D and J gene segment including those combinations listed in instant claims 37 and 38 with a reasonable expectation of success, and to 1) immunize these mice according to Logtenberg et al. and Murphy et al., 2) obtain human kappa light chain and human heavy chain variable sequences from B cells isolated from the immunized mice, 3) operatively link both the heavy and light chain variable sequences to human constant region sequence, and 4) express the sequences within a mammalian host cell to produce a fully human antigen specific antibody with a reasonable expectation of success.
No claims are allowed.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634