DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims status
Applicants reply filed 10/14/2025 is acknowledged.
Claims 2, 4-10, 13-16 is/are cancelled. Claims 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 is/are currently pending and is/are under examination.
Specification - Maintained
The following objection to the specification was not addressed by the Applicant in the remarks filed 10/14/2025, thus it is reiterated below. Appropriate correction is required.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
For e.g. Valenzuela et. al. in at least [0099] and WIPO publications in at least [0106]. The disclosure from the NPL Valenzuela et. al. is not essential since a similar disclosure is also provided by the US6586251, also referenced with. See 37 C.F.R.1.57(d) for the definition of “essential material”. However, if the Applicant disagrees with the finding that Valenzuela provides essential material then Applicant is requested to follow the guidance above.
The disclosure from the WIPO publications in [0106] are essential material to provide written description support for instant claims 18 and 19. Only U.S. patents or U.S. patent application publications can be properly incorporated by reference. Applicant may amend the specification to recite the U.S. patents and/or U.S. patent application publications that are associated with the WIPO publications referenced. Alternatively, Applicant may follow the guidance above.
Claim Suggestion - Reiterated
The following suggestion to improve claim language was not addressed by the Applicant in the remarks filed 10/14/2025, thus it is reiterated below.
Claim 19 recites “wherein the RAG2 gene and the IL-2RG gene have been disrupted”. Since claim 19 is a product claim, following language -that avoids active verbs- is more appropriate: “further comprising disrupted disrupted IL-2RG gene
Appropriate correction is recommended.
Claim Rejections - 35 USC § 112(b) – Maintained in part
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.
Rejection of Claims 3, 10, 19, 21, 23, 25 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 is withdrawn in light of claim amendments and cancellations.
Claims 37-40 remain 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 method step of “assaying”. The metes and bounds of this step are indefinite because no structure is provided for this step i.e. what or how the assay is conducted.
Claims 38-40 is/are rejected due their dependence on claim 37 because they do not clarify the 112b issue noted with claim 37.
Claim Rejections - 35 USC § 112(d) - Moot
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Rejection of Claim 4 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is moot due to claim cancellation.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENUSL.—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.
Written Description
Rejection of Claims 1-12, 14, 15, 17-19, 21, 23, 25-27, 34, 37-40 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 is withdrawn in light of amendments, such as to claims 1 and 18 that limit the claimed genetically modified mouse or rat to one with the specifically claimed structure that finds support in the instant specification.
Scope of Enablement
Rejection of Claims 1-12, 14, 15, 17-19, 21, 23, 25-27, 34, 37-40 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the scope of enablement requirement is withdrawn in light of amendments, such as to claims 1 and 18 that limit the claimed genetically modified mouse or rat to one with the specifically claimed structure that finds support in the instant specification.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Rejection of Claim(s) 2, 4-10, 13-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Herndler-Brandstetter et al (PNAS, 114 (45) E9626-E9634, doi.org/10.1073/pnas.1705301114 (2017). hereinafter Brandstetter), Human CXCL13 gene and protein sequences (NM_006419.2, July 2008; NP_006410.1, sequence derived from GenBank# AF044197.1, BI836728.1, CA418514.1, each submitted before 2012) and Mouse Cxcl13 gene and protein sequences (NM_018866.2, Nov 2006; NP_061354.1, sequence derived from GenBank# AC146611, submitted 2004) in view of Kazanietz et al (Front. Endocrinol. 10:471. doi: 10.3389/fendo.2019.00471) as evidenced by Valenzuela et al (Nature Biotech 21(6), June 2003; IDS 5/19/2023) and Rongvaux et al (Nature Biotech, doi:10.1038/nbt.2858, March 16, 2014; IDS 5/19/2023) is moot due to claim cancellation.
Previous rejection of Claim(s) 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 under 35 U.S.C. 103 as being unpatentable over Herndler-Brandstetter et al (PNAS, 114 (45) E9626-E9634, doi.org/10.1073/pnas.1705301114 (2017). hereinafter Brandstetter), Human CXCL13 gene and protein sequences (NM_006419.2, July 2008; NP_006410.1, sequence derived from GenBank# AF044197.1, BI836728.1, CA418514.1, each submitted before 2012) and Mouse Cxcl13 gene and protein sequences (NM_018866.2, Nov 2006; NP_061354.1, sequence derived from GenBank# AC146611, submitted 2004) in view of Kazanietz et al (Front. Endocrinol. 10:471. doi: 10.3389/fendo.2019.00471) as evidenced by Valenzuela et al (Nature Biotech 21(6), June 2003; IDS 5/19/2023) and Rongvaux et al (Nature Biotech, doi:10.1038/nbt.2858, March 16, 2014; IDS 5/19/2023) is withdrawn in light of amendment to claims 1, 18, 21, 26, 34.
Claim(s) 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Herndler-Brandstetter et al (PNAS, 114 (45) E9626-E9634, doi.org/10.1073/pnas.1705301114 (2017). hereinafter Brandstetter), Human CXCL13 gene and protein sequences (NM_006419.2, July 2008; NP_006410.1, sequence derived from GenBank# AF044197.1, BI836728.1, CA418514.1, each submitted before 2012) and Mouse Cxcl13 gene and protein sequences (NM_018866.2, Nov 2006; NP_061354.1, sequence derived from GenBank# AC146611, submitted 2004) in view of Kazanietz et al (Front. Endocrinol. 10:471. doi: 10.3389/fendo.2019.00471) as evidenced by Valenzuela et al (Nature Biotech 21(6), June 2003; IDS 5/19/2023) and Rongvaux et al (Nature Biotech, doi:10.1038/nbt.2858, March 16, 2014; IDS 5/19/2023).
Regarding claim 1, Brandstetter teaches genetically modified mice comprising in its genome a humanized gene, wherein the humanized gene is formed as a result of replacement of endogenous mouse genomic DNA sequences with orthologous human genomic DNA sequences at the endogenous mouse gene locus such that the humanized gene encodes the humanized protein comprising the endogenous mouse signal peptide with the mature human protein sequence and the mouse expresses the mature human protein (Figure 1E, 1G, Materials and Methods: Mice). Brandstetter teaches several humanized mice, for example humanized IL15 mouse (Figure 1E, Materials and Methods: Mice). In case of genetically modified mice comprising in its genome a humanized IL-15 gene, Brandstetter teaches the humanized IL-15 gene that comprises the mouse exons 1-4 of the mIL-15 gene to preserve the endogenous IL-15 signal peptide and comprises human exons 5-8 and 3’UTR of hIL-15 gene that encodes the mature human IL-15 protein (Figure 1 legend). Brandstetter also teaches the use of a well-known method to generate humanized mice i.e. Velocigene (Materials and Methods: Mice). This method has been previously described in several publications as evidenced by Valenzuela et al and also in Rongvaux et al.
Regarding claims 12, Brandstetter teaches inserting the humanized gene at the endogenous mouse locus such that the humanized gene is operably linked to the endogenous mouse promoter.
Regarding claim 17, Brandstetter teaches humanized mice that are homozygous for the humanized gene (Figure 1G shoes SRG-15h/h).
Regarding claim 21, Brandstetter isolated several tissues and cells from their humanized mice that comprise the humanized gene formed as a result of replacement of endogenous mouse genomic DNA sequences with orthologous human genomic DNA sequences at the endogenous mouse gene locus such that the humanized protein produced by the humanized gene comprises the endogenous mouse signal peptide with a mature human protein sequence (Figures 2-5).
Regarding claims 23, 25-27, Brandstetter teaches the method of making a genetically modified mouse wherein the mouse genome is modified to comprise the humanized gene and mouse with modified genome is made (Materials and Methods: Mice). The modification step of Brandstetter inherently comprises the steps recited in claims 26 and 27 because Brandstetter’s method is same as the method of Valenzuela since Brandstetter also uses Velocigene method of Valenzuela (Materials and Methods: Mice). Valenzuela evidences that modification step of Brandstetter inherently comprise introducing the humanized gene comprising the human gene nucleic acid sequence in a mouse ES cell to obtain an ES cell with the humanized gene (=isolated ES cells comprising humanized gene, required for claim 23) inserted at the endogenous locus – resulting in replacement of some of the mouse gene nucleic acid sequences with human gene nucleic acid sequences- and generating a humanized mouse using the obtained ES cell (=mouse comprising ES cell which produces or is produced by mouse embryo comprising ES cells as required by claim 25; Methods: ES cell growth, electroporation and genomic DNA isolation and Screening of ES cell clones using ‘loss-of-native-allele’ assay).
Regarding claim 34, Brandstetter teaches design of targeting nucleic acid constructs for targeting endogenous mouse genes for humanization (Figure 1E).
Brandstetter teaches the need for generating humanized mice that express human gene required for human immune cell function by noting that “As such, humanized mice represent a promising model for studying human immune function and diseases in vivo and could be used to screen and identify highly effective combinations of cancer therapeutics. However, the poor interspecies cross-reactivity of factors that are essential for the physiological and functional development of human immune cells in humanized mice highlights the need to improve the currently available humanized mice” (e9626, left column, para 3). They identify IL-15 as “one such cytokine, with only 65% of amino acids identical between humans and mice” yet is “essential for the development and/or function of NK cells, memory CD8 T cells, CD8αα intraepithelial lymphocytes (IELs), and tissue-resident NK cells” (e9626, left-right column, bridging para). They show that using a humanized mouse which comprises “knock-in replacement of the mouse Il15 coding sequence by the human IL15 coding sequence had the advantage of proper expression of physiological levels of IL-15 in a tissue- and cell-specific manner, as opposed to DNA or protein injection. Engrafted SRG-15 mice showed improved functional development of circulating and tissue-resident human NK and CD8+ T cells” (e9627, left column, para 1). Therefore, Brandstetter teaches that humanized mice comprising replacement of an endogenous gene required for immune cell function with a human version of that gene such that the mouse expresses the mature protein product of the human gene results in improved engraftment of human cells in the humanized mouse.
Brandstetter does not teach Cxcl13 gene or protein sequences or a humanized mouse comprising humanized Cxcl13 gene.
However, sequences for both human and mouse Cxcl13 gene were publicly available and taught by NM_006419.2 and NM_018866.2. These sequences show the location of each exon in these genes, the sequence encoding signal peptides in these genes as well as the sequence encoding the mature protein. Furthermore, the sequence for both human and mouse Cxcl13 protein were publicly available and taught by NP_006410.1 and NP_061354.1.
The human Cxcl13 protein sequence NP_006410.1 teaches the residues (#23-109) comprised in the mature proteins sequence which is 100% identical to instant SEQ ID No: 2 (as required for claim 3). The human Cxcl13 gene sequence NM_006419.2 teaches that the nucleotides (#79-144) and exons (exon 2) encode the human Cxcl13 protein signal peptide while the nucleotides (#145-405) and exons (exons 3, 4 and nucleotides 357-405 of exon 5) encode the human mature Cxcl13 protein (as required for claim 11).
The mouse Cxcl13 gene sequence NM_018866.2 teaches that the nucleotides (#33-95) and exons (exons 1) encode the mouse Cxcl13 protein signal peptide (as required for claim 11) while the nucleotides (#96-362) and exons (exons 2-4) encode the mouse mature Cxcl13 protein.
Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the well-known Velocigene method also used by Brandstetter to generate a humanized Cxcl13 mouse comprising a humanized Cxcl13 gene wherein the mouse Cxcl13 gene exons encoding the mouse mature Cxcl13 protein sequences (exons 2-4 or nucleotides #96-362), taught by NM_018866.2, are replaced with human Cxcl13 gene exons encoding the human mature Cxcl13 protein sequences (exons 3, 4 and nucleotides 357-405 of exon 5 or nucleotides #145-405), taught by NM_006419.2. Such a humanization strategy would result in a humanized Cxcl13 mouse comprising a humanized Cxcl13 gene wherein the exons (exon 1) from mouse Cxcl13 gene that encode the mouse Cxcl13 protein signal peptide (i.e. endogenous mouse Cxcl13 signal peptide) are retained while exons (exon 3-5) from human Cxcl13 gene that encode the human Cxcl13 mature protein replace the mouse exons (2-4) that encode the mouse Cxcl13 mature protein. Such a configuration would allow for retention of mouse signal peptide in the humanized Cxcl13 gene and is motivated by the teaching from Brandstetter regarding mouse signal sequences/ propeptide for proper processing of the human protein (Figure 1 legend).
Furthermore, regarding claims 26, 27, it would be obvious to an ordinary artisan before the effective filing date of the claimed invention to use the method used by Brandstetter to generate the humanized Cxcl13 mice by substituting Brandstetter humanized gene with the humanized Cxcl13 gene rendered obvious by the combination of Brandstetter and NM_018866.2, NM_006419.2. Similarly, regarding claim 34, it would be obvious to an ordinary artisan before the effective filing date of the claimed invention to use the targeting vector design of Brandstetter to generate a mouse humanization Cxcl13 gene targeting vector which would comprise human CXCL13 nucleic acid sequences taught by NM_006419.2- to be integrated at the endogenous mouse Cxcl13 locus- flanked by 5’ and 3’ homology arms that are homologous to the mouse Cxcl13 gene (NM_018866.2) allowing for insertion of human CXCl13 sequences.
An ordinary artisan would be motivated to generate such a humanized Cxcl13 mouse because of the teachings of Brandstetter regarding the need to generate humanized mice for genes that are important for proper development and function of human immune cells and teachings from Kazanietz that teaches that Cxcl13 such a gene. Kazanietz teaches that Cxcl13 is important for normal B-cell development and trafficking, important for attracting B-cells via chemotaxis (paras 2, 3 in section CXCL13 CHEMOKINE: THE LIGAND FOR CXCR5). Furthermore, Cxcl13 plays a role in recruitment of malignant B-cells in lymphomas and leukemias (para 1 in section CXCL13 IN LYMPHOPROLIFERATIVE DISEASES AND LYMPHOMA).
An ordinary artisan would reasonably expect to generate such a humanized Cxcl13 mouse because the methods to generate humanized mouse are well-known, especially Velocigene which was first taught in Valenzuela in 2003 and has been used since to generate several humanized mice comprising humanized various genes that are important for proper human cell development and function in mice. For example, Brandstetter use Velocigene to generate humanized Sirpa and humanized IL-15 mice. Rongvaux also evidences successful use of Velocigene to generate three humanized genes: TPO, IL-3, M-CSF (Online Methods: Mice). Furthermore, the sequences required to generate humanized Cxcl13 gene to comprise mouse Cxcl13 gene sequences and human CXCL13 gene sequences using the Velocigene methods were publicly available and taught by NM_006419.2 and NM_018866.2.
Regarding claims 18, 19, Brandstetter teaches a genetically modified mouse comprising humanized Sirpa gene and RAG2/IL2-RG knockout (=disrupted; SRG in Figure 1) that support engraftment of human CD45+ cells and human T-cells in mice (Figure 1, B-D; Supplementary figure S1). The genetically modified mouse comprising humanized Sirpa gene taught by Brandstetter comprises the humanized Sirpa gene comprising exon 1 of the endogenous rodent Sirpa gene, exons 2-4 of a human SIRPA gene, and exons 5-8 of the endogenous rodent Sirpa gene, and the humanized Sirpa gene is operably linked to the rodent Sirpa promoter at the endogenous rodent Sirpa locus (Figure 1A). Brandstetter further teaches crossing the SRG mice with the humanized IL-15 gene mouse to generate mice that allow engraftment of human NK-cells as well due to the presence of the human IL-15 protein in these mice (Figure 2).
Therefore, it would be obvious to a person of ordinary skill in the art to cross the SRG mice of Brandstetter with the humanized Cxcl13 mouse, rendered obvious by the combination of Brandstetter, Human CXCL13 gene and protein sequences and, Mouse Cxcl13 gene and protein sequences in view of Kazanietz, to generate a SRG mouse with humanized Cxcl13 gene. An ordinary artisan would be motivated to generate such a cross (i.e. SRG x humanized Cxcl13) because it would allow for additional engraftment of human B-cells, which are supported by human Cxcl13 protein in the humanized mouse. An ordinary artisan would use routine mouse breeding methods to cross SRG mice with humanized Cxcl13 mice.
Regarding claims 37-40, Brandstetter teaches the methods of use of humanized mice to test anti-cancer candidate agents for treating cancer, wherein the humanized animal is engrafted with Raji human lymphoma cancer cells (=introduce step) and injected with Rituximab (=contacting step) to assay the efficacy of the anti-cancer agent in reducing or eliminating the human cancer cells (Figure 6, Tumorigenesis). Considering Kazanietz teaches the Cxcl13 plays a role in recruitment of malignant B-cells in lymphomas and leukemias (para 1 in section CXCL13 IN LYMPHOPROLIFERATIVE DISEASES AND LYMPHOMA), it would be obvious to an ordinary artisan before the effective filing date of the claimed invention to use the humanized Cxcl13 mice- rendered obvious by the combination of Brandstetter, Human CXCL13 gene and protein sequences and, Mouse Cxcl13 gene and protein sequences in view of Kazanietz - in the method of using humanized mice to test candidate anti-cancer agents taught by Brandstetter. Since Kazanietz teaches that the Cxcl13 plays a role in lymphomas and leukemia, an ordinary artisan would be motivated to use the humanized Cxcl13 mouse to test anti-lymphoma and anti-leukemia cancer agents (as required for claim 38-40). An ordinary artisan would substitute the humanized Cxcl13 mice in Brandstetter’s method to predictably yield a method as claimed.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant’s arguments with respect to the U.S.C. 103 rejection of claim(s) 1-12, 14-19, 21, 23, 25-27, 34, and 37-40 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Arguments pertinent to the instant the U.S.C. 103 rejection of claim(s) 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 are addressed below.
1. Applicant argue that “The cited art is silent as to a rodent having the structural components as specifically claimed” (referencing claim limitations added to claim 1; page 13, para 4). In response, each of the claim limitation added to claim 1 is addressed in the instant U.S.C. 103 rejection.
2. Applicant argue lack of motivation to combine Brandstetter with any or all the other cited materials to arrive at Applicant's amended claim 1 (page 13-14, bridging para). In support, Applicant allege that “the passage in Brandstetter relied upon by the Office cannot be interpreted as suggesting that a humanized mouse should be created for any gene that is important for proper development and function of human immune cells.” because the Applicant believe that “The list of such genes is potentially enormous”. Further, Applicant allege that, in their understanding, “that passage of Brandstetter may be read to suggest the need to improve the currently available humanized mice (e.g., the then existing mice models with human IL-15 being introduced); however, the passage does not suggest the need for generating new humanized mice. Finally, even if Brandstetter is seen as suggesting the improvement of the currently available humanized mice, the need for the improvement Brandstetter suggests would be for "poor interspecies cross-reactivity of factors that are essential for the physiological and functional development of human immune cells in humanized mice". Brandstetter, p. E9626 first column. However, there is no evidence of record showing that Cxcl13 is a molecule having poor interspecies cross-reactivity”. (page 14, para 2)
In response, the sequences of human and mouse Cxcl13 proteins (NP_006410.1 and NP_061354.1) cited in the previous and the instant U.S.C. 103 rejection provide evidence that “that Cxcl13 is a molecule having poor interspecies cross-reactivity” based on Brandstetter’s teachings regarding such molecules. For example, Brandstetter, p. E9626 states “However, the poor interspecies cross-reactivity of factors that are essential for the physiological and functional development of human immune cells in humanized mice highlights the need to improve the currently available humanized mice (9). One such cytokine, with only 65% of amino acids identical between humans and mice, is interleukin 15 (IL-15).” (emphasis added). Only 44% of amino acids are identical between human and mouse Cxcl13 proteins (see Sequence alignment between NP_006410.1 and NP_061354.1 in PTO-892). Thus, even if the list of genes that are important for proper development and function of human immune cells maybe enormous, based on Brandstetter’s and Kazanietz teachings, humanizing mouse Cxcl13 protein is high on that list due to its low homology with human Cxcl13 protein and the importance of human Cxcl13 protein in human immune system and disease.
Finally, argument regarding improving available humanized mice vs new humanized mice is unclear. Brandstetter indeed generates a “new” humanized mouse line wherein the new mouse line is a cross between previously available and widely used immunodeficient mouse line and the humanized IL15 mouse. Using immunodeficient mouse lines as a base to form new mouse lines with humanized genes is common practice and one used in the instant specification as well. In fact the only mouse line produced in the instant specification is, similar to Brandstetter, generated by delivering a humanized construct to mouse ES cells from SRG immunodeficient mouse, same as Brandstetter [102].
3. Applicant allege without evidence that “the skilled artisan would not necessarily have had a reasonable expectation that a humanized rodent as specifically claimed would successfully produce the human mature CXCL13 protein in the serum of rodent” (page 14-15, bridging para).
In response, Applicant provide no evidence that a skilled artisan does not expect that a that a humanized rodent as specifically claimed would successfully produce the human mature CXCL13 protein. As noted in the previous and the instant U.S.C. 103 rejection, the methods to generate humanized mouse were well-known, especially Velocigene which was first taught in Valenzuela in 2003 and has been used since to generate several humanized mice comprising humanized various genes that are important for proper human cell development and function in mice. For example, Brandstetter use Velocigene to generate humanized Sirpa and humanized IL-15 mice and production of hIL-15 in the mouse serum (Figure 1G). Rongvaux also evidences successful use of Velocigene to generate three humanized genes: TPO, IL-3, M-CSF (Online Methods: Mice). Thus, the expectation of an artisan using the Velocigene method to humanize mouse genes is that the humanized mouse produces human protein.
4. Applicant argue unexpected and superior results alleging that “the cited art does not disclose the use of the claimed rodent to provide an improved animal system that promotes survival/proliferation of engrafted human cells” such as allegedly shown in Figure 3 which compares SRG-BA6-13 mice (SIRPahu/hu Rag2-/- IL2Rg-/- and humanized BAFF, APRIL, IL-6, and CXCL13) to NSG control mice and separately SRG-BA6 mice (SIRPahu/hu Rag2-/- IL2Rg-/- and humanized BAFF, APRIL, IL-6) to NSG control mice.
In response, at first it must be noted that the claimed rodent is not SRG-BA6-13 mouse but only a humanized CXCL13 rodent. Thus, the alleged properties cannot be ascribed to the humanization of CXCL13 alone. Furthermore, the data does not clearly establish that any alleged difference between the SRG-BA6-13 mice and SRG-BA6 mice are indicative of superiority, and that this superiority statistically and practically significant (see MPEP 716.02(b)I). For example, the patient samples tested for the two proliferation assays are clearly different as is evident by different proliferation rates observed in the NSG mice (comparing SRG-BA6-13 mice with NSG vs comparing SRG-BA6 mice with NSG in Figure 3-left-top vs bottom). This difference in samples tested in the two proliferation assays makes it difficult to compare the two assays. Therefore, with these data, it cannot be concluded that SRG-BA6-13 mice show higher proliferation in comparison to SRG-BA6 mice. A direct comparison between SRG-BA6-13 mice and SRG-BA6 mice using the same patient samples in both mice needs to be performed to make any conclusions regarding proliferation differences between these mice. Data presented in Figure 3-right-top vs bottom showing survival could not be compared either since while the top graph shows percent of CD19+CD5+ cells in SRG-BA6 vs NSG mice, the bottom graph shows number of CD19+CD5+ cells/ ul in SRG-BA6-13 vs NSG mice. Therefore, with these data, it cannot be concluded that SRG-BA6-13 mice show higher survival in comparison to SRG-BA6 mice.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632