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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/12/2026 has been entered.
Claims status
Claims 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 is/are currently pending and is/are under examination.
Specification - Withdrawn
The objection to the specification is withdrawn due to amendment to specification.
Claim Rejections - 35 USC § 112(b) – Withdrawn
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 37-40 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendment.
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) 18 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 to address the newly added claim limitation.
Claim(s) 1, 3, 11, 12, 17-19, 21, 23, 25-27, 34, 37-40 remain and claim 18 is 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). Brandstetter teaches that RAG2/IL2-RG knockout are immunodeficient (Introduction, para 2; newly added claim limitation). 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) 18 have been considered but are moot because the new ground of rejection necessitated by claim amendments.
Applicant's arguments filed with respect to the U.S.C. 103 rejection of claim(s) 1-12, 14-17, 19, 21, 23, 25-27, 34, and 37-40 have been fully considered but they are not persuasive.
1. 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, para 2). Applicant point to pp.15-16 in OA dated 1/12/2026 that stated “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” (emphasis added) and “Only 44% of amino acids are identical between human and mouse Cxcl13 proteins” to conclude that “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” (emphasis added). In response, Applicant allege that “Poor interspecies cross-reactivity is not necessarily based on sequence identity” relying on alleged teachings from Bossen, Liu, Ma and Chihara (page 13, para 4, page 14). Applicant also argue that based on R&D product recombinant mouse CXCL13 that has an ability to chemoattract mouse B-cells transfected with human CXCR5 “one of skill in the art would have known at the time the instant application was filed in 2022 that mouse Cxcll3 activated the human CXCR5 receptor, i.e., there was indeed cross-species reactivity” (page 15, para 1).
In response, regarding Liu, Ma and Chihara discussed on page 14, para 2, two non-identical ligands, such IL-34 and M-CSF, can bind the same receptor, CSF1R. Many such receptors are known, Kainate receptor that binds glutamate and kainite or Glycinergic receptors that bind glycine and GABA. This does not indicate cross-species reactivity or lack thereof, Il-34 and M-CSF could simply bind different regions of the CSF1R; as suggested by Wei in Introduction, para 3, last line.
Regarding Chihara, Applicant state “However, despite substantial sequence identity between human and mouse IL-34, human IL-34 did not bind mouse Fms" (Chihara et al., Results)).” (emphasis added; page 14, para 2). Applicant do not point out where in Chihara Results is the sequence identity of human and mouse IL-34 compared and regarded as “substantial”.
Critically, conclusion presented in OA dated 1/12/2026 was based on teachings from the prior art of Brandstetter’s that is in the same field of endeavor as the instant application. In this field of humanizing a mouse model to have a humanized immune system, the relevant criterion for interspecies cross-reactivity is noted by Brandstetter. In vitro assays, such as Bossen, Liu, Ma, Chihara and R&D systems, could show a more significant cross-species reactivity however there relevance to the field of humanized mouse model is not established. In fact, well before the publication of Brandstetter, it was known that human and mouse IL-15 have cross-reactivity with mouse and human IL-15Ra in vitro. See Abstract from Eisenman et al (Cytokine, Vol. 20, No. 3, 2002). Yet, “with only 65%” amino acid identity between human and mouse IL-15, Brandstetter was motivated to humanize the mouse with human IL-15 gene. Similarly, Rongvaux states “Although mouse and human TPO are both-sided cross-reactive to the respective cognate receptors when used at supraphysiological doses in vitro, affinity and biologic activity might differ when the cytokine acts at limiting, physiological doses in context of an in vivo environment, particularly in the microenvironment of the HSC niche in the bone marrow. We thus hypothesized that mouse TPO might not provide an appropriate stimulus to the human c-Mpl receptor in vivo and, therefore, could account for the impaired properties of human HSCs in the mouse environment.” (emphasis added; page 2378, col. 2, last para). Thus, Rongvaux develop a humanized TPO mouse. Thus, the relevant prior art did not rely on in vitro cross-reactivity assays, such as Bossen, Liu, Ma, Chihara and R&D systems, rather was motivated to humanize cytokines known for key functions in human immune cell development and diseases, especially with low sequence identity, since it might provide an appropriate stimulus to the human cells in vivo.
2. 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 16, para 1).
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.
3. 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 (page 16, para 2). In response to the analysis presented in OA dated 1/12/2026 wherein it was noted that the comparisons of data presented for the two mouse lines (SRG-BA6-13 vs SRG-BA6) cannot be compared, Applicant point to [0110] which states “2-3 mice of each strain were xenografted with the same patient sample” and "No obvious difference of CLL cell frequency (hCD19+hCD5+hCD3-) and their proliferation status (Trace Violet-low or CFSE-low) was observed between NSG and SRG-BA6 strains. In contrast, proliferation (4 out of 5 patient samples) and CLL cell number (3 out of 3 patient samples) were markedly increased in SRG-16 BA6-13 mice, as compared to NSG mice (FIG. 3)" (page 16-17, bridging para). Based on these data and statements, Applicants allege that a skilled artisan would appreciate a “noticeably distinct trend” despite the variability and that “the precise measure would not have an effect on the trends observed relative to the NSG controls” (page 17). Further, to show that the NSG controls in the two data set are equivalent, Applicant chose to compare the range of proliferation of 5 of the NSG controls from the SRG-BA6 group with the range of proliferation of 4 of the NSG controls from the SRG-BA6-13 group.
In response, as noted previously, 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, despite Applicant’s allegations, 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).
Regarding the samples used in the two sets of data shown in Figure 3, the statement “2-3 mice of each strain were xenografted with the same patient sample” from the specification does not mean that the same patient samples were used in the two sets of experiment. It means for each experiment, 2-3 mice were xenografted with the same sample such that for example in the SRG-BA6 data set, 2-3 SRG-BA6 mice got the same patient sample. It does not mean that the NSG cohort used for SRG-BA6 data set is the same as the SRG-BA6-13 data set. Furthermore, to show equivalency of the NSG controls in the two data set, an ordinary artisan would not pick and chose only 5 mice from one data set and compare them a range from the other data set. An Mean±SD or median would be the expected comparator and if an animal is deemed an outlier then it should be removed from the data set. Thus, as noted previously, an ordinary artisan cannot compare these data sets because of apparent differences in the control groups. 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.
Regarding different measures used in the two data sets, for example, % cells for one data set and cell number/ul in the other, an ordinary artisan would recognize that indeed the precise measure would affect the trend. A sample may show an increase in concentration of a cell type in the sample as the cells in that sample proliferate but also a reduction in percent of that cell type because other cells in the sample proliferated faster resulting in a higher percent of the other cells.
Therefore, with these data, it cannot be concluded that SRG-BA6-13 mice show higher survival or engraftment in comparison to SRG-BA6 mice. Of note, claimed mice is not SRG-BA6-13.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632
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