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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Claims 1-3, 5, 8-11, 29-30, 33, 35, 39-41, 61, 67, 70, 73, and 76 were previously pending.
Receipt is acknowledged of the claim amendments filed on 10 December, 2025. Claims 1, 3, 5, 9-11, 29-30, 33, 35, 39-41, 61, 67, 70, 73, 76 are amended. Claims 2, and 8 are cancelled. Claims 83-84 are newly added.
Claims 61, 67, 70, 73, and 76 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1, 3, 5, 9-11, 29-30, 33, 35, 39-41, and 83-84 are pending and under examination in the instant Official Action. Claim 1 is the only independent claim.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CN2020/142546, filed 31 December, 2020, which claims priority to People’s Republic of China Application No. CN201911408385.4, filed 31 December, 2019. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified untranslated copies of papers required by 37 CFR 1.55 have been filed in this application on 29 June, 2022.
The earliest possible priority for the instant application is 31 December, 2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 26 February, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The Drawings submitted on 29 June, 2022 are accepted by the Examiner.
Withdrawn Objections/Rejections in view of Applicant’s Amendments/Arguments
Claim Objections
The objection to claims 1-3, 5, 9-11, 29-30, 33, 35, and 39-41 because abbreviations/acronyms need to be spelled out upon their first encounter in the claims (For example: SIRPα, CD132, IgV, CD27, CD28, ITIM, TNFR, CD137, TNF, and CD47) is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended the claims to spell out all previously identified abbreviations/acronyms.
The objection to claims 9, 10, and 39 because they are missing the proper indefinite, e.g, “a” or “an” or definite, e.g., “the” articles in from of various nouns is withdrawn in view of Applicant’s amendments to the claims. Applicant has corrected the previously identified issues.
Claim Rejections - 35 USC § 112
The rejection of claims 2, 3, 5 and 35 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 applicant regards as the invention is withdrawn in view of Applicant’s amendments to the claims.
Maintained Objections/Rejections in view of Applicant’s Amendments/Arguments
Claim Objections
Claim 41 remains objected to because of the following informalities: The claim is missing the proper indefinite, e.g, “a” or “an” or definite, e.g., “the” articles in from of various nouns. Appropriate correction is required.
In amended claim 41, line 5, the noun “human” should be preceded by either “a” or “the”, e.g., the human or a human. The same is required for each recitation of “mouse” in claim 41. Care should be taken to avoid raising new issues of indefiniteness. Appropriate correction is requested.
Claim Rejections - 35 USC § 112
Claims 1, 3, 9-11, 29-30, 33, and 39-41 remain rejected and new claims 83-84 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention. This rejection has been modified as necessitated by Applicant’s amendments to the claims.
While applicants’ amendment partially overcome some of the issues related to the previously claimed genus of genetically modified non-human animals, some additional issues remain that are discussed below. The amended claims are broadly directed to a genetically modified mice whose genome comprises a genus of chimeric SIRPα proteins comprising any humanized SIRPα extracellular region, any mouse SIRPα transmembrane region, and any mouse SIRPα cytoplasmic region, and another genus chimeric SIRPα proteins comprising any humanized SIRPα extracellular region, any mouse SIRPα transmembrane region, and any mouse SIRPα cytoplasmic region and a chimeric CD47 comprising any human or humanized CD47 extracellular Ig-like V-type (IgV) region and five mouse CD47 transmembrane domains. Mice of the subsequent genera are claimed with the contemplated function of determining the effectiveness of an agent and to be able to determine the toxicity of an anti-SIRPα or an anti-CD47 antibody. Note that, withdrawn claims 61 and 70 read function into the SIRPα/CD47 sequences within the claimed animal model in that withdrawn claims 61 and 70 require the SIRPα and/or CD47 to be able to determine the toxicity of an anti-SIRPα or an anti-CD47 antibody. The claims do not state with any specificity what structures are required within the SIRPα or the CD47 to enable the screening of antibodies targeting them. It is noted that amended claim 1, requires a “humanized” rather than a “human” SIRPα extracellular region and that said “a humanized SIRPα extracellular region” requires no particular sequence or components.
Applicants are claiming an undefined number of polypeptides having any humanized SIRPα extracellular region, any mouse SIRPα transmembrane region, and any mouse SIRPα cytoplasmic region and an undefined number of polypeptides having any human or humanized CD47 extracellular Ig-like V-type (IgV) region and five mouse CD47 transmembrane domains. The specification teaches that SIRPα acts as an inhibitory receptor which interacts with CD47 and discusses targeting both of these molecules as a therapy and teaches that recapitulating the human SIRPα-CD47 interface is desirable in an animal model used for discovery of such therapeutics (Specification, [0290]-[0292]). The specification also teaches that the humanized SIRPα may have the amino acid sequence shown in SEQ ID NO: 53 or 62 and teaches that a sequence having homology as low as 60% to either of these sequences may be used (Instant specification, [0325]-[0326], [0342]). The specification does not explicitly state that the humanized SIRPα associated with SEQ ID NO: 53 or 62 is a mouse SIRPα having a replacement of the IgV region with that of a human SIRPα. However, the specification extensively discusses the SIRPα IgV domain and states that the “donor region is largely within the extracellular Ig-like V-type domain” (Instant specification, [0295]-[0300]). Thus, it appears that the humanized portion of the SIRPα of the instant invention is “largely within” the IgV region of SIRPα. The specification is silent as to what portions of SEQ ID NO: 53 or 62 are responsible for the IgV functionality nor which residues may be modified to which amino acids to still retain IgV functionality and cognate CD47 interaction. With regard to CD47, the specification prophetically teaches that any domain within CD47 can be replaced with a corresponding human sequence in the instant invention and that such sequences may be as low as 50% identical to the wild-type human sequence (Specification, [0367]). The specification teaches more specifically that the donor region for the humanized CD47 is the IgV domain (Specification, [0358]), and that the resulting humanized CD47 may be as low as 60% identical to SEQ ID NO: 75 (Specification, [0382]). As is the case with SIRPα, the specification does not specifically state that SEQ ID NO: 75 corresponds with a humanized mouse CD47 having the mouse IgV region replaced with a human CD47 IgV region. However, the discussion of replacement of the CD47 IgV region coupled with the disclosure of the specific SEQ ID NO: 75 produces an inference that the IgV region is precisely what is replaced within SEQ ID NO: 75. The specification is silent as to what portions of SEQ ID NO: 75 are responsible for the IgV functionality nor which residues may be modified to which amino acids to still retain IgV functionality and cognate SIRPα interaction. This disclosure is not deemed to be descriptive of the complete structure of a representative number of polypeptide sequences encompassed by the instant claims as one of skill in the art cannot envision all of the variants of SIRPα and CD47 functionally able to preserve their native interaction to enable the screening of anti-SIRPα and anti-CD47 antibodies. The working examples are specific to chimeric SIRPα having SEQ ID NO: 53 and chimeric CD47 having SEQ ID NO: 75 (Specification, [0672], [0688]), and there is no disclosure of any actual variants of these two humanized polypeptides nor any extracellular, transmembrane, and cytoplasmic regions other than the specific sequences contained within SEQ ID NO: 53 and 75. Hence, there is no structure/function relationship taught at all for the residues within SEQ ID NO: 53 or 75 let alone which of the 513 or 326 amino acids respectively can be changed to which amino acids to still retain SIRPα-CD47 interaction. To the extent that a structure/function relationship can be gleaned from the instant specification, it is with respect to the specific SEQ ID NO: 53 for SIRPα and the specific SEQ ID NO: 75 for CD47 (Specification, [0672], [0688]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). Further, A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See MPEP 2163(II)(A)(3)(a)(ii).
In disclosing only two humanized SIRPα (SEQ ID NO: 53 and 62) and only a single humanized CD47 (SEQ ID NO: 75), applicant has not disclosed a representative number of species for the entire genus claimed because the claimed genus covers species in which the donor human SIRPα region may vary by an undefined number of amino acids and the donor human CD47 may vary by an undefined number of amino acids, and the replaced amino acids may be any amino acids (including a contiguous string of prolines or even tryptophans). A skilled artisan would understand that any protein having a substitution of 98 contiguous amino acids to prolines would cease to have much in common with the unsubstituted variant, let alone a 154 amino acid long stretch, and that the same can be said for amino acids having large aliphatic side chains like tryptophan, and that such humanized SIRPα and CD47 polypeptides would have their affinity for each other significantly impacted by such substitutions. Hence, the structure/function correlation of a polypeptide is unpredictable, and a skilled artisan would recognize that the vast genus claimed encompasses polypeptides whose function would be hindered if not abolished by specific amino acid substitutions.
The skilled artisan understands that one nucleotide change in a DNA molecule or one amino acid change in the polypeptide encodes by the DNA molecule could result in loss of it’s biological activity as demonstrated in the generation of sickle-cell anemia wherein one specific amino acid mutation gives rise to the inherited disease (Voet et al., Biochemistry, John Wiley and Sons, 1990, p. 126-129). Further, the skilled artisan also understands that the significance of particular amino acids within a peptide cannot be predicted a priori but must be determined from case to case by painstaking experimental study (Rudinger, J., Peptide Hormones. Palgrave, London, 1976. 1-7. (Page 6, “Conclusions”)) and that it is not known whether there exists an algorithm for predicting the structure of a given protein from its amino acid sequence alone (Ngo et al., The protein folding problem and tertiary structure prediction. Boston, MA: Birkhäuser Boston, 1994. 433-506. (page 492, second full paragraph)). The specification prophetically teaches that an undefined genus of polypeptides having 60% identity to SEQ ID NO: 53 and of polypeptides having 60% identity to SEQ ID NO: 75 will have the function of retaining SIRPα-CD47 affinity and enable screening of anti-SIRPα and anti-CD47 antibodies (Specification, [0290]-[0292]). However, the specification is silent as to what residues within SEQ ID NO: 53 and 75 are responsible for the functional properties observed for full-length SEQ ID NO: 53 and 75. Thus, a skilled artisan would understand from the teachings of Voet, Rudinger, and Ngo that the results of changing any given amino acid within SEQ ID NO: 53 or 75 would be unpredictable and that it would require significant experimentation to determine which variants of SEQ ID NO: 53 and 75 would still possess the desired function.
The claims encompass an undefined number of polypeptides having any humanized SIRPα extracellular region, any mouse SIRPα transmembrane region, and any mouse SIRPα cytoplasmic region and an undefined number of polypeptides having any human or humanized CD47 extracellular Ig-like V-type (IgV) region and five mouse CD47 transmembrane domains. The specification has only exemplified a polypeptide having the amino acid sequence of SEQ ID NO: 53 and one having the amino acid sequence of SEQ ID NO: 75 as possessing the functional properties. Thus, Applicant has not disclosed a representative number of species for the entire genera of mice claimed.
Response to Arguments
Applicant argues “claim 1 has been amended to recite that "[a] genetically-modified mouse whose genome comprises at least one chromosome comprising a sequence encoding a chimeric signal regulatory protein a (SIRPa) protein, wherein the mouse is immune-deficient; wherein the chimeric SIRPa protein comprises a humanized SIRPa extracellular region, a mouse SIRPa transmembrane region, and a mouse SIRPa cytoplasmic region"; and claim 30 has been amended to recite, in part, that "wherein the mouse further comprises a sequence encoding a chimeric CD47 protein, wherein the chimeric CD47 protein comprises a human or humanized CD47 extracellular Ig-like V-type (IgV) region and five mouse CD47 transmembrane domains."
Applicant submits that the present application provides ample support for amended
claims 1 and 30, and the as-filed specification explicitly discusses the humanization schemes of the SIRPa and CD47 genes. For example, Table 3 of the present application specifically shows that the replaced region in mouse SIRPa gene (as discussed in Examples 4-5) corresponds to nucleic acids 538- 861 in NM_007547.4 (SEQ ID NO: 78), and this region encodes amino acids 32-139 in NP_031573.2 (SEQ ID NO: 79); and Table 1 of the present application specifically shows that the region for replacement in human SIRPa gene corresponds to nucleic acids 118-441 in NM_080792.2 (SEQ ID NO: 76), and this region encodes amino acids 31-138 in NP_542970.1 (SEQ ID NO: 77). In the paragraph following Table 1, the present application states that: The extracellular region of human SIRPa comprises an Ig-like V-type domain and two Ig- like Cl-type domains. According to the information of human SIRPa from the UniProt Database (UniProt identifier: P78324), the Ig-like V-type domain, the Ig-like C1-type 1 domain, and the Ig-like C 1-type 2 domain correspond to amino acids 32-137, amino acids 148-247, and amino acids 254-348 of the human SIRPa protein (SEQ ID NO: 77; or NP_542970.1). Specifically, the Ig-like V-type domain, the Ig-like Cl-type 1 domain, and the Ig-like Cl-type 2 domain are encoded by a portion of exon 3, a portion of exon 4, and a portion of exon 5 of human SIRPa (SEQ ID NO: 77). Thus, the donor region is largely within the extracellular Ig-like V-type domain (N-terminal IgV domain). (As-filed specification, page 33, last two lines and page 34, lines 1-7; emphasis added) Similarly, Table 7 of the present application specifically shows that the replaced region in mouse CD47 gene (as discussed in Example 6) corresponds to nucleic acids 200-505 in NM_010581.3 (SEQ ID NO: 82), and this region encodes amino acids 23-124 in NP_034711.1 (SEQ ID NO: 83); and Table 5 of the present application specifically shows that the region for replacement in human CD47 gene corresponds to nucleic acids 247-558 in NM_001777.3 (SEQ ID NO: 80), and this region encodes amino acids 23-126 in NP_001768.1 (SEQ ID NO: 81). In the paragraph following Table 5, the present application states that: According to the information of human CD47 from the UniProt Database (UniProt identifier: Q08722), the extracellular Ig-like V-type domain corresponds to amino acids 19-127 of the human CD47 protein (SEQ ID NO: 81; or NP_001768.1), and the five transmembrane domains correspond to amino acids 142- Specifically, the extracellular Ig- like V-type domain is encoded by a portion of exon 2 of human CD47 gene. Thus, the donor region is located within the extracellular Ig-like V-type domain (N-terminal IgV domain). (As-filed specification, page 44, lines 2-7; emphasis added) Applicant submits that by comparing the encoded amino acid sequences of the replaced gene fragments and the location of the IgV domain in human SIRPa or CD47 proteins, a POSITA would have understood the humanization schemes of the SIRPa and CD47 genes.” (Remarks, pages 12-13). This argument has been fully considered but has not been found persuasive for the following reasons.
Even the excerpted language from the specification that Applicant has provided here is specific to particular amino acid sequences (all found within SEQ ID NO: 53 and 75) which are not claimed in amended claim 1 nor amended claim 30. Amended claim 1 broadly construed does not even require an IgV domain within the SIRPα protein because it only requires “a humanized SIRPα extracellular region”. This language is incredibly non-specific and encompasses “a” region with only one of the two Ig- like Cl-type domains located within the full-length wildtype human SIRPα as well as “a” extracellular region that has been humanized from another organism which has an entirely extracellular domain with an entirely different IgV domain. The specification has only exemplified a SIRPα having the amino acid sequence of SEQ ID NO: 53 as possessing the functional properties required for the practice of the invention. The same can be said of the broad language in amended claim 30 with respect to CD47 domains and the specification’s only exemplifying SEQ ID NO: 75.
Applicant also argues “Applicant further notes that MPEP §2163 indicates that "information which is well known in the art need not be described in detail in the specification." As discussed in Murata, Y., etal. "The CD47-SIRPa signalling system: its physiological roles and therapeutic application." The Journal of Biochemistry 155.6 (2014): 335-344 (submitted herewith as Exhibit A), states that "[t]he N-terminal IgV-like domain of SIRPa trans-interacts with the IgV-like domain of CD47. The binding of CD47 to SIRPa promotes the tyrosine phosphorylation of the latter protein" (Exhibit A, page 336 under Fig. 1). Fig. 1 of Exhibit A is reproduced below. CeliACellB Fig. 1 of Exhibit A Thus, the IgV domains are particularly important for binding between SIRPaL and CD47 proteins, which can promote downstream signaling pathways via other regions or domains. As the structures of human SIRPa~ and CD47 proteins, as well as the function of each domain thereof, were known in the art at the time when this application was filed, Applicant respectfully submits that Applicant is not required to provide detailed information regarding what was well known in the art.” (Remarks, pages 13-14). This argument has been fully considered but has not been found persuasive for the following reasons.
While the interaction between the IgV domains of CD47 and SIRPα is well known in the art, what is not well known in the art is the extent of modifications that can be made to said IgV domains or any of the other domains of each respective polypeptide to retain said CD47-SIRPα IgV interaction. This is the issue with the breadth of amended claims 1 and 30 coupled with the limited disclosure of only mice having the amino acid sequence of SEQ ID NO: 53 and of mice having the amino acid sequence of SEQ ID NO: 75 having retained such interaction between CD47 and SIRPα. Accordingly, this argument has been fully considered but has not been found persuasive.
Claim Rejections - 35 USC § 103
Claims 1, 3, 9-11, 29-30, 33, 35, and 39-41 remain rejected and claims 83-84 are newly under 35 U.S.C. 103 as being unpatentable over CN108531487 (Published: 14 September, 2018) (English Machine Translation attached, hereinafter “Chen”) (of record) in view of Siolas et al. Cancer research 73.17 (2013): 5315-5319 (hereinafter “Siolas”), Walsh et al. Annual Review of Pathology: Mechanisms of Disease 12.1 (2017): 187-215 (hereinafter “Walsh”), and CN108588126 (Published: 28 September, 2018) (English Machine Translation attached, hereinafter “Bai”). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Regarding claim 1, Chen discloses a mouse comprising a human SIRPα gene and a human CD47 gene wherein the human genes are not on the same chromosome within the mouse (Chen, page 24, “Embodiment 11” heading). Chen teaches that CRISPR-Cas9 was used to generate the mouse (Chen, pages 18-21, starting at “Embodiment 1” heading). It is noted that the resulting SIRPα gene is chimeric as taught by Chen (Chen, page 18, “Embodiment 1” heading). Chen claims a humanized animal model having a humanized SIRPα having human SIRPα extracellular region, mouse transmembrane region, and mouse intracellular region (Chen, claim 2). Thus, Chen discloses a genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a chimeric SIRPα wherein the chimeric SIRPα comprises a humanized extracellular region with mouse transmembrane and cytoplasmic regions. Chen also teaches that SIRPα plays an important role in a variety of immunological processes, that SIRPα has great application value in tumor and immune treatment fields, and that their mouse expressing human SIRPα gene is useful for screening and evaluating SIRPα protein expression and gene function and for screening anti-tumor medicines (Chen, page 2, last paragraph, page 3, last paragraph, page 4, first three paragraphs).
Chen does not disclose that the mouse is immune deficient as required by instant claim 1.
Siolas teaches that xenograft mouse models which are based on the transfer of primary tumors directly from a patient into an immunodeficient mouse are useful for the development of anticancer therapies and personalized medicine (Siolas, Abstract). Siolas also teaches that tumors from xenograft mice more closely resemble the original clinical cancer than long-established cell lines and that xenograft mouse models are broadly used and are a powerful tool for studying tumor biology and for evaluating anticancer drugs (Siolas, page OF2, second full paragraph). Thus, a person having ordinary skill in the art would have been motivated by the teachings of Siolas to have used a xenograft mouse model for evaluating anticancer drugs because such a tool is taught by Siolas as powerful for doing so.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have used an immunodeficient mouse as taught by Siolas to generate the mouse model expressing SIRPα of Chen and to have arrived at the invention claimed in instant claim 1 with a reasonable expectation of success because both Chen and Siolas teach the usefulness of these technologies for the evaluation of anticancer drugs, and a person having ordinary skill in the art would have been motivated to do so to enable them to leverage the powerful tool that Siolas teaches xenograft mice models to be. A skilled artisan would have had a reasonable expectation of success because generating immunodeficient mice models was known in the art before the effective filing date of the claimed invention.
Regarding claim 3, Chen claims insertion of SIRPα such that the endogenous regulatory elements control the human SIRPα gene (Chen, claims 1-2).
Regarding claim 9, Chen teaches that the endogenous SIRPα is not expressed in the mouse (Chen, page 5, “(a)” heading).
Regarding claim 10, Chen claims the animal expresses the human SIRPα in its cells (Chen, claim 1).
Regarding claim 11, Chen teaches that the SIRPα gene comprises an extracellular IgV-like domain (Chen, page 2, second to last paragraph), and teaches that the invention comprises the replacement of the mouse SIRPα exon 2 with corresponding human SIRPα sequence (Chen, page 13, last paragraph; page 18, “Embodiment 1” heading; page 26, second to last paragraph; claim 3). While, Chen does not explicitly teach that mouse SIRPα exon 2 corresponds with the IgV-like domain, this property is inherent as evidenced by the instant specification which teaches that mouse SIRPα exon 2 corresponds with human SIRPα exon 3 (Instant Specification, page 35, lines 14-20), and that human SIRPα exon 3 encodes the Ig-like V-type domain (Instant Specification, page 34, lines 1-7).
Regarding claim 29, Chen claims multiple gene humanized mice wherein the first humanized gene is SIRPα and the other gene(s) are selected from PD-1, CD27, CD28, CTLA-4, LAG-3, BTLA, PD-L1, TIGIT, TIM-3, GITR, CD137, or OX-40 (Chen, claims 22-23).
Regarding claims 30 and 33, Chen also claims multiple gene humanized mice wherein the first humanized gene is SIRPα and another humanized gene is CD47 (Chen, claims 22-23). Chen does not teach wherein the chimeric CD47 comprises a human or humanized CD47 extracellular Ig-like v-type (IgV) region and five mouse CD47 transmembrane regions, nor does Chen teach insertion of the CD47 at the endogenous locus with operable linkage to the endogenous CD47 promoter.
Bai teaches a humanized animal model wherein the animal comprises a human CD47 extracellular region inserted into the endogenous CD47 gene such that the resulting chimeric CD47 is under control of the endogenous CD47 promoter (Bai, page 4, “invention content” heading). Bai also teaches that inhibiting the CD47-SIRPα signal path can generate an effective treatment for tumors (Bai, page 2, last paragraph), that a CD47 humanized mouse would allow for the screening of drugs to target CD47 as a therapy (Bai, page 3, last paragraph), and that their method of inserting human CD47 into the endogenous locus reduces or eliminates expression of the endogenous CD47 of animal origin (Bai, page 4, “invention content” heading). Bai specifically teaches that CD47 has five transmembrane domains and that their chimeric CD47 has human CD47 IgV domain and mouse transmembrane domains (Bai, page 2, third paragraph; page 4, fourth and fifth paragraphs). It is noted that both Bai and Chen share authors with each other. Thus, a person having ordinary skill in the art would not have to look far when developing multiple humanized mouse models as taught by Chen for a suggested strategy for inserting human CD47 into said mouse, because Bai and Chen are from the same research group. A person having ordinary skill in the art would have been motivated to use the chimeric CD47 of Bai in the mouse model of Chen to enable the screening of drugs to target CD47 as a therapy. Further, a person having ordinary skill in the art would have been motivated by the teachings of Bai to have selected the endogenous locus for insertion of the human CD47 such that the resulting gene would be under control of the endogenous promoter because Bai suggests to do so to reduce or eliminate endogenous CD47 expression and produce a model for the screening of CD47 targeting drugs.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have selected the endogenous locus for insertion of the human CD47 in the multiple humanized mouse model of Chen such that the resulting gene would be under control of the endogenous promoter and arrive at the invention claimed in instant claims 30, and 33 because Bai suggests to do so to reduce or eliminate endogenous CD47 expression and produce a model for the screening of CD47 targeting drugs.
Regarding claim 35, Bai discloses SEQ ID NO: 74 which is a 100% match to instant SEQ ID NO: 75 (Bai, page 5, second paragraph) (see below).
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Regarding claim 39, the CD47 insertion of Bai eliminates expression of the endogenous CD47.
Regarding claim 40, Bai claims the animal’s cells express the human CD47 gene (Bai, claim 1).
Regarding claim 41, Bai teaches that the chimeric CD47 is mouse CD47 with human exon 2 (Bai, page 4, sixth paragraph; page 14, paragraph five).
Regarding claim 83, Chen teaches that the extracellular region comprises an IgV-like domain (Chen, page 2, fourth paragraph) and Chen claims a humanized animal model having a humanized SIRPα having human SIRPα extracellular region, mouse transmembrane region, and mouse intracellular region (Chen, claim 2).
Regarding claim 84, neither Chen, nor Siolas teaches the disruption of the animal’s endogenous CD132 gene as required by instant claim 84.
Walsh teaches that humanized mice have become important preclinical tools for biomedical research, and that this has been motivated by the continuous improvement of immunodeficient recipients used to generate humanized mice (Walsh, page 188, second paragraph). Walsh also teaches that a key breakthrough in this field in recent years was the development of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (Walsh, page 188, second paragraph). Walsh also teaches three existing strains lacking IL2 receptor common gamma chain (two of which completely lack the entire gene), and teaches that, when engrafted with human cells, the biological responses in humanized IL2 receptor common gamma chain null mice more faithfully recapitulate those seen in humans than in any previous humanized mouse models (Walsh, page 188, third paragraph). It is noted that CD132 is another name for IL2 receptor common gamma chain. Thus, a person having ordinary skill in the art evaluating prospective genetic backgrounds for development of xenograft mice for the evaluation of anticancer therapeutics would have been motivated by Walsh to have used a CD132 KO mouse background to more faithfully recapitulate the biological responses seen in humans.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have used a CD132 knockout (KO) mouse as taught by Walsh as the genetic background for the development of the SIRPα xenograft mice of Chen and Siolas and to have arrived at the invention claimed in instant claim 84 with a reasonable expectation of success because they would have been motivated to do so to more faithfully recapitulate the biological responses seen in humans which would better inform therapeutic strategies.
Therefore, claims 1, 3, 9-11, 29-30, 33, 35, 39-41, and 83-84 are rejected for being obvious over Chen, Siolas, Walsh, and Bai.
Response to Arguments
Applicant argues “there would have been no motivation to combine Chen and Siolas to arrive at the claimed inventions. Chen discloses a genetically-modified mouse whose genome comprises a chimeric SIRPa gene encoding a humanized SIRPa protein. In Example 13 of Chen, the mouse was inoculated with modified mouse colon cancer cell line MC38-hCD47 to test different anti-SIRPa antibodies' anti-tumor effects. Chen concludes in Example 13 that:
The above research results prove that the humanized SIRPa animal model can be used as a living model for in vivo drug efficacy research, used for the screening, evaluation and treatment experiments of SIRPa signaling pathway regulators, and can be used to evaluate the effectiveness of antibodies targeting human SIRPa in animals, and evaluate the therapeutic effect of targeting SIRPa, etc. (Chen, English machine translation of paragraph [0362]; emphasis added) Siolas discloses tumor graft models (also known as patient-derived xenografts or PDX). The models are built by transfer of primary tumors directly from the patient into an immunodeficient mouse (see abstract of Siolas). The immunodeficiency character of the mouse can prevent rejection by the host immune system, thereby allowing the primary tumors to grow to desirable sizes for better evaluation of anti-cancer drugs. Siolas states that:"PDX models may be superior to traditional cell line xenograft models of cancer because they maintain more similarities to the parental tumors" (see page OF2, left column of Siolas). Siolas further concluded that PDX models are not widely used, partially because its high cost to develop and maintain, long latency periods after engraftment, and lack of broad availability. Applicant submits that a POSITA would not have been motivated to combine Chen and Siolas because Chen used traditional cell line xenograft models, e.g., by inoculating the host mouse with MC38-hCD47 cells, and obtained satisfactory results. According to FIG. 20 and Table 10 of Chen, the tumors in the control group (G1) continued to grow during the experimental period. Thus, there would have been no need to establish an immunodeficient background of the host mouse to further promote tumor growth.” (Remarks, pages 15-16). This argument has been fully considered but has not been found persuasive for the following reasons.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, both Chen and Siolas teach the usefulness of their respective technologies for the evaluation of anticancer drugs, and a person having ordinary skill in the art would have been motivated to combine the teachings of Chen and Siolas to enable them to leverage the powerful tool that Siolas teaches xenograft mice models to be. There is not reason provided by Applicants of why inoculation of colon cancer cell line MC38-hCD47 resulting in Chen’ s tumors in the control group (G1) which continued to grow during the experimental period could not have been grafted into an immune deficient mouse of Siolas as easily as other cell lines. In fact, mouse xenografts models derived from tumor cells have been successfully used by cancer biologists for decades (Siolas, Introduction, P 2)
As Applicant acknowledged, Siolas teaches the superiority of their PDX models to the traditional cell line xenograft models used in Chen. Therefore, a person having ordinary skill in the art would have also been motivated to use the immunodeficient PDX xenograft mouse for the expression of the chimeric SIRPα polypeptides of Chen to produce a superior mouse model for screening drugs. Accordingly, this argument has been fully considered and is not found persuasive.
Applicant also argues “the present application states in relevant part that: However, these humanized CD47/SIRPa animal models are not suitable for testing the phagocytosis effects of these antibodies as many of them may induce antibody-dependent cellular cytotoxicity (ADCC) or some other immune responses. Those effects can skew the results and make it difficult to evaluate phagocytosis. The genetically modified animals as described herein do not have functional T cells or B cells, but they still have functional phagocytic cells, e.g., neutrophils, eosinophils (acidophilus), basophils, or monocytes. Macrophages can be derived from monocytes, and can engulf and digest cellular debris, foreign substances, microbes, cancer cells. Thus, the genetically modified animals described herein can be used to determine the effect of an agent (e.g., anti- CD47 antibodies or anti- SIRPa antibodies) on phagocytosis, and are particularly useful for determining the effects of the agent to inhibit the growth of tumor cells. Therefore, the genetically modified animals with humanized SIRPa and/or CD47 as described herein provide an advantageous model to test the effects of anti-hCD47 antibodies or anti-hSIRPa antibodies on phagocytosis. Furthermore, the genetically- modified animals described herein can be injected with human PBMC or CD34+ cells for immune system reconstitution. As functional endogenous macrophages and granulocytes remain in B-NDG mice, B-NDG mice with humanized CD47/SIRPa gene after immune system reconstitution provides an immune system that is even more similar to that of human, which is particularly useful for testing agents that target human immune system. (As-filed specification, page 30, lines 28-31 and page 31, lines 1-14; emphasis added) Thus, the claimed genetically-modified mouse models provide advantages, e.g., by allowing the phagocytosis effects of anti-CD47 antibodies or anti-SIRPa antibodies being tested with minimal interference from undesirable immune responses (e.g., ADCC) induced by the tested antibodies. Such an advantage is demonstrated by the experiments in Example 8 of the present application, which shows that a combination of an anti-human CD20 antibody (0.1 mg/kg) and an anti-SIRPa antibody (10 mg/kg) exhibited a synergistic anti-tumor effect (see FIG. 19). The synergistic anti-tumor effect can be visualized by the different survival curves of group G4 and groups G2-G3” (remarks, page 16). This argument has been fully considered but has not been found persuasive for the following reasons.
In response to applicant's argument that the invention possesses advantages over the prior art, it is noted that the features upon which applicant relies (i.e., The genetically modified animals as described herein do not have functional T cells or B cells, but they still have functional phagocytic cells, e.g., neutrophils, eosinophils (acidophilus), basophils, or monocytes) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims only require “immune deficient”. Further, no evidence or argument has been submitted to attempt to distinguish the argued advantage as an unexpected or superior result of rendering a mouse immune deficient. Accordingly, this argument has been considered but has not been found persuasive.
In response to Applicant’s argument that the mouse claimed has the same advantage to that of Chen, it is unclear how this would overcome the obviousness of the claimed invention over Chen in view of Siolas. This argument appears to just state an advantage to using the humanized SIRPα expressing mouse of Chen and does nothing to preclude the combination of Chen and Siolas. Accordingly, this argument is not found to be persuasive.
Double Patenting
Claims 1, 3, 5, 9-11, 29-30, 33, 35, and 39-41 remain rejected and newly added claims 83-84 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,973,212 B2 in view of CN108531487 (Published: 14 September, 2018) (English Machine Translation attached, hereinafter “Chen”), Siolas et al. Cancer research 73.17 (2013): 5315-5319 (hereinafter “Siolas”), Walsh et al. Annual Review of Pathology: Mechanisms of Disease 12.1 (2017): 187-215 (hereinafter “Walsh”), and CN108588126 (Published: 28 September, 2018) (English Machine Translation attached, hereinafter “Bai”).
The reference claim 1 claims: “A genetically-modified mouse whose genome comprises a chimeric SIRPα gene encoding a chimeric SIRPα protein, wherein the chimeric SIRPα gene comprises a replacement of a portion of mouse SIRPα gene exon 2 with a portion of human SIRPα gene exon 3, wherein the chimeric SIRPα gene further comprises mouse SIRPα gene exon 3 and mouse SIRPα gene exon 4, wherein the mouse expresses the chimeric SIRPα protein.”
The instant amended claim 1 claims “A genetically-modified mouse whose genome comprises at least one chromosome comprising a sequence encoding a chimeric signal regulatory protein α (SIRPα) protein, wherein the mouse is immune-deficient, and wherein the chimeric SIRPα protein comprises a humanized SIRPα extracellular region, a mouse SIRPα transmembrane region, and a mouse SIRPα cytoplasmic region.”
The reference claim 1 is narrower than the instant claim 1 with the specific recitated replaced portions within SIRPα and it is broader than instant claim 1 in that it does not require the animal to be immune deficient.
With regard to the ways in which the reference claim 1 is narrower than instant claim 1, this relationship can be best described as a species-genus relationship. 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).
With regard to the instantly claimed limitation requiring the animal to be immune deficient, Siolas teaches and provides motivation to use an immune deficient mouse (see above 103 rejection).
With regard to instant dependent claim limitations which differ from the reference patent (lacking CD132, human or chimeric CD47, etc.), Chen, Bai, and Walsh teach and provide motivation to produce an animal model with all of the instantly claimed characteristics.
Therefore, instant claims 1, 3, 5, 9-11, 29-30, 33, 35, and 39-41 would have been prima facie obvious to a person having ordinary skill in the art over the reference patent in view of Chen, Siolas, Walsh, and Bai.
Response to Arguments
Applicant argues against the nonstatutory double patenting rejection by arguing that the scopes of the claims are different because the instant amended claim 1 requires the mouse to be “immune-deficient” and by reiterating the above arguments against the application of Siolas. These arguments have been fully considered but have not been found persuasive for the same reasons identified in response to the arguments above.
New Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 112
Claim 11 is newly 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. This rejection has been necessitated by Applicant’s amendments to the claims.
Amended claim 11 recites “a portion of” various exons without setting forth how much of the exons must be included to be considered “a portion”. Thus, the metes and bounds of amended claim 11 are unclear and a person having ordinary skill in the art would not be apprised of the scope of the patent protection sought.
Additional Comments
Claim 5 is indicated as free of the prior art of record. Chen claims SEQ ID NO: 26 which is a 99% match to instant SEQ ID NO: 53 (Chen, claim 7) (see below). However, none of the prior art of record discloses the entirety of SEQ ID NO: 53.
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Conclusion
Claims 1, 3, 5, 9-11, 29-30, 33, 35, 39-41, and 83-84 are rejected.
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.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634