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 .
Claim Status
Claims 1-33 are pending.
Claims 2, 5-6, 8-9 and 14-33 are withdrawn.
Claims 1, 3-4, 7 and 10-13 are under examination.
New Claim Objections
Claim 10 is objected to because of the following informalities:
Claim 10 includes periods before the end of the claim (“c.2041 C >T” and “c.6513T > A”). Periods are only allowed at the end of a claim. Applicant is directed to MPEP 608.01(m) which states “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).”
Appropriate correction is required.
Election/Restrictions
Note that newly submitted claims 32-33 are directed to species that are independent and distinct from the elected species for the following reasons:
Newly added claims 32-33 are drawn to a murine subject that is wild type with respect to Rag1, which is an unelected species type of “mutation type” as originally presented in the species election requirement set forth on 4th, August, 2025. Applicant previously elected the species of “homozygous mutation in Rag1” and therefore the newly added limitation of “wild type with respect to Rag1” encompasses structurally and functionally distinct unelected species that do not include Applicant’s elected species.
Since applicant has received an action on the merits for the originally presented invention and species, this species has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 32-33 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claims 1, 3-4, 7 and 10-13 are under examination.
Withdrawn Claim Rejections - 35 USC § 112(a)
Written Description
The rejection of claim 4 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paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-4, 7 and 10-13 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A humanized xenograft murine model comprising a murine subject genetically engineered to be deficient in Cxcl10;
wherein the murine subject genetically engineered to be deficient in Cxcl10 is
a Rag1-/- mouse,
a Cxcl10-/- mouse,
a CD4-deficient mouse homozygous for the Cd4tm1Mak targeted mutation,
a CD8-deficient mouse homozygous for the Cd8atm1Mak targeted mutation,
a CD4/CD8-deficient mouse homozygous for the Cd8atm1Mak targeted mutation and homozygous for the Cd4tm1Mak targeted mutation,
a NOD/SCID mouse homozygous for the mutation Prkdcscid,
a Ccl5-/- mouse, or
a Cx3cr1-/- and Ccr2-/- mouse deficient in the expression of microglia or T cell chemokine receptors;
and a population of human cells in the nervous system of the animal.
does not reasonably provide enablement for
All other genetically engineered mutation types that result in “deficiency in CXCL10”
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Instant claims encompass:
“murine subject is genetically engineered to be deficient in Cxcl10” (claim 1 and dependents )
This includes murine subjects that are deficient in Cxcl10 due to all possible genetic modifications that would cause deficiency in Cxcl10 including all possible mutations of all possible types that result in deficiency in Cxcl10 that are genetically engineered by all possible methods. Furthermore, this includes genetic alterations at all possible alterations of all possible points in all possible pathways that affect the amount of Cxcl10 in all possible ways and result in a deficiency of Cxcl10.
Direction or Guidance Presented
While contemplating all possible murine subjects that are genetically engineered to be deficient in Cxcl10, Applicant provides limited guidance on preparing the xenograft model with specific transgenic mice that include specific mutations (Example 1). Importantly the instant specification provides broad and non-specific guidance on making the murine subjects with the deficiency in CXCL10 required by the claimed invention (pg. 26). For the working Examples, commercially available mice and crossbreeds of commercially available mice were used and no specific mouse was made by the disclosure.
Present Working Examples
Example 1 (pg. 43-65)
In Example 1, Applicant prepares a xenograft mouse model.
Human cells types: NF1-null (mutation in the NF1 gene is c.2041 C >T or c.6513T > A)
Implantation location: brainstem of mice
Mouse Types:
Rag1-/- (B6.129S7-Rag1tm1Mom/J; strain 002216, Jackson laboratories)
Cxcl10-/- (B6.129S4-Cxc/10tm1Adl/J; strain 006087, Jackson laboratories)
CD4-deficient (B6.129S2-Cd4tm1Mak/J; strain 002663, Jackson laboratories)
CD8-deficient (B6.129S2-Cd8atm1Mak/J; strain 002665, Jackson laboratories)
CD4/CD8-deficient (intercrossed strains 002663 and 002665)
NOD/SCID (NOD. Cg-Prkdcscid/J; strain 001,303, Jackson laboratories)
Ccl5-/- (B6.129P2-Cc5tm1Hso/J; strain 005090; Jacksonlaboratories)
Cx3cr1-/-, Ccr2-/- mice (see also Figure 11).
Both NF1-null iNPC lines formed LGGs at 1 mpi in approximately 50% of mice injected.
Human cells types : K/AA1549:BRAF-expressing iNPCs
Implantation location: cerebella of mice
Mouse Types:
Rag1-/- (B6.129S7-Rag1tm1Mom/J; strain 002216, Jackson laboratories)
Over 85% of all Rag1-/- mice injected with K/AA1549:BRAF-expressing iNPCs formed LGGs at 1mpi (see e.g., FIG. 3A-FIG. 3B).
Absent Working Examples
Applicant does not provide a working example with guidance on obtaining or making species of murine subjects that are genetically engineered to be deficient in Cxcl10 other than the mice of Example 1, which all appear to be commercially available mice and crossbreeds of commercially available mice.
State of the Prior Art and Unpredictability of the Art
Animals “Engineered to be Deficient in Cxcl10”
As stated above (see breadth of the claims above), Applicants claim encompasses all mutation types at all points in all pathways that would result in the claimed deficiency in CXCL10. Genetically engineering murine subjects to have a particular phenotype is not predictable.
The instant specification does not provide any guidance on the specific targeting sequences, and/or gene editing endonuclease that results in the required mutation for the Cxcl10 deficiency or any specific guidance for other engineering methods. These elements are required for one of ordinary skill to reasonably make and use the full breadth of murine subjects encompassed by instant claims. As stated above, the guidance provided by Applicant is broad and non-specific.
Applicant is directed to the art of Flora et al. (accessed at: https://www.taconic.com/resources/why-a-transgenic-design-project-fails#:~:text=The%20phenotype%20of%20a%20transgenic,new%20mouse%20models10%2C11). Flora evidences results obtained using transgenic lines oftentimes not translate to clinical studies (pg. 2). Flora further evidences the phenotype of a transgenic animal can fail due to erroneous modifications of the targeted allele and insertion of off-target mutations in the genome (pg. 3-4). Flora evidences characteristics of the targeted locus might lead to detrimental deletion of functional genomic elements, resulting in phenotypes not correlated with the desired gene modification and further evidences that careful evaluation of the genomic structure of the target locus might not be sufficient if the vector for the generation of the transgenic line contains elements that negatively influence the functionality of the model (pg. 3).
Applicant is additionally directed to the post-filing art of Hay et al. (Adv Exp Med Biol. 2022;1354:279–297.; henceforth “Hay”). Hay evidences that even-post filing, making transgenic animals with a desired phenotype is unpredictable. Specifically, Hay evidences unintended mutations, a phenomenon known as off-targeting, may lead to compromised health or an unexpected phenotype (pg. 6). Hay further evidences that editing in embryos may result in a mosaic genotype rather than a complete expression (pg. 6 3rd para.).
Therefore, because making a specific gene mutation in all animal types is not predictable, Applicant is not enabled for all animal types that have been engineered to be deficient in Cxcl10.
Unpredictability of the Art and the Quantity of Experimentation Necessary
Unpredictability of the Art
As the arts of Flora and Hay demonstrate, the obstacles that hinder the preparation of the claimed xenograft model are not easy tasks to be done or solely routine experimentation to enable particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to make and use the instant broadly claimed invention.
Scope of Enablement - Conclusion
In conclusion, the full breadth of the claims lack enablement because the specification provides broad and non-specific guidance in making the murine subject with the mutations of the claims to arrive at the claimed functional result of a deficiency in CXCL10. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot predictably be performed. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.
Response to Arguments
Applicant’s arguments, filed 30th, March, 2026, have been fully considered but are not found persuasive.
Applicant argues the amendments overcome the rejection (pg. 8).
In response, for the reasons set forth above, because the required structure of genetically engineering a murine subject to have a deficiency is not predictable for the reasons set forth above, one of ordinary skill would not have been able to make and use the murine subjects of instant claims.
New Claim Rejections - 35 USC § 112 (b)
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.
Claim 3 is 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 3 recites the broader “the animal engineered to be deficient in Cxcl10” together with the narrower “murine model.” A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
Furthermore, claim 3 is also indefinite because it recites “the animal” while claim 1, upon which claim 3 depends, does not recite an animal. Therefore, the scope of this claimed term is unclear and the metes and bounds of the term are indefinite.
Withdrawn Claim Rejections – 35 USC § 102
The rejection of claims 1 and 11-12 under 35 U.S.C. 102(a)(1) as being anticipated by Selek et al. (J Neurosci Methods. 2014 Jan 15:221:159-65. Epub 2013 Oct 11.; henceforth “Selek”) as evidenced by Blumberg et al. (JCI Insight. 2022 Jun 8;7(11):e155682.;henceforth “Blumberg”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 1, 4, 7, 10 and 13 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Mo et al. (J Clin Invest. 2021 Jan 4;131(1):e139807.; First Published 27th, October 2020; henceforth “Mo”) as evidenced by Pan et al. (Genes Dev. 2018 Apr 1;32(7-8):491–496.; see IDS filed 14th, February, 2024;henceforth “Pan”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments to recite that the murine subject is “genetically engineered” to be deficient in CXCL10.
Response to Declaration under 37 CFR 1.130
The Declaration under 37 CFR 1.130 filed 30th, March 2026 is insufficient to disqualify the prior at of Mo et al. (J Clin Invest. 2021 Jan 4;131(1):e139807.; First Published 27th, October 2020; henceforth “Mo”) because the prior art reference of Mo was published online as a pre-print on 27th, October, 2020 and therefore the reference was “accessible to persons concerned with the art to which the document relates” as of the date of first publication of 27th, October, 2020, which is more than a year before the earliest effective filing date of the instant Application, and therefore this prior art cannot be overcome by the 35 USC § 102(b)(1)(A) exception.
The publisher’s website clearly indicates that the Mo reference was first published 27th, October, 2020. This is clearly indicated in the copy of the reference provided with the non-final Office action mailed on 29th, December, 2025, which is copied below for reference.
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Applicant is directed to MPEP 2128 which states that an electronic publication, including an online database or Internet publication (e.g., discussion group, forum, digital video, or social media post), is considered to be a "printed publication" within the meaning of 35 U.S.C. 102(a)(1) and pre-AIA 35 U.S.C. 102(a) and (b) provided the publication was accessible to persons concerned with the art to which the document relates. See In re Wyer, 655 F.2d 221, 227, 210 USPQ 790, 795 (CCPA 1981). MPEP 2128 further states that electronic publications on the internet or on an online database are considered to be publicly available as of the date the item was publicly posted.
The prior art of Mo was published online as a pre-print on 27th, October, 2020 and therefore the reference was “accessible to persons concerned with the art to which the document relates” as of the date of first publication of 27th, October, 2020.
Therefore, the date of 27th, October, 2020, which the reference was posted as a pre-print in accordance with the publisher’s website, is the public availability date of the Mo reference, and because this is more than a year before the earliest effective filing date of the instant Application, this prior art cannot be overcome by the 35 USC § 102(b)(1)(A) exception.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 1, 3 and 11-12 under 35 U.S.C. 103 as being unpatentable over Selek et al. (J Neurosci Methods. 2014 Jan 15:221:159-65. Epub 2013 Oct 11.; henceforth “Selek”) in view of Huang et al. (J Immunol. 2014 Aug 1;193(3):1496-503.;henceforth “Huang”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 4, 7 and 10 under 35 U.S.C. 103 as being unpatentable over Selek et al. (J Neurosci Methods. 2014 Jan 15:221:159-65. Epub 2013 Oct 11.; henceforth “Selek”) in view of Huang et al. (J Immunol. 2014 Aug 1;193(3):1496-503.;henceforth “Huang”) as applied to claim 1 above, and in further view of Mo et al. (J Clin Invest. 2021 Jan 4;131(1):e139807.; First Published 27th, October 2020; henceforth “Mo”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New 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.
Claims 1, 3-4, 7, 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over He et al. (FASEB J. 2019 Jan;33(1):140-150. Epub 2018 Jun 26.; henceforth “He”) in view of Mo et al. (J Clin Invest. 2021 Jan 4;131(1):e139807.; First Published 27th, October 2020; henceforth “Mo”).
Regarding claim 1, He discloses a humanized xenograft murine model comprising:
A murine subject (Sprague Dawley (SD) rats);
wherein the murine subject is genetically engineered to be deficient in Cxcl10 (“We knocked out Rag1, Rag2, and Il2rg” abstract; see also Methods pg. 141 col. 2)
However, regarding claim 1, although He teaches the severely immunodeficient SD-RG rats support fast growth of patient derived xenografts as compared with mice, thus holding great potential to serve as a newmodel for oncology research (abstract), He is silent to including a xenograft, a population of human cells, in the nervous system of the animal.
Nevertheless, regarding claim 1, Mo teaches implanting a population of hiPSCs with a c.2041 C >T or c.6513T > A mutation in NF1 (pg. 16 2nd para.) into a xenogenic murine model (“mouse sciatic nerve implantation”; abstract) to investigate human neurofibroma pathogenesis (abstract), to create an accurate humanized in vivo neurofibroma models (pg. 3 2nd para.) and to generate proliferating SCPs and examine the impact of NF1 mutations on Schwann cell lineage differentiation, as well as generate human neurofibromas (pg. 3 3rd para.) to serve as tractable platforms for drug identification and screening, as well as to provide unprecedented opportunities to elucidate the mechanisms underlying neurofibroma development and progression (pg. 3 3rd para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the xenograft murine model of He, and combine the known prior art element of the implant of hiPSCs with a c.2041 C >T or c.6513T > A mutation in NF1 of He to obtain the predictable result of a xenograft model. One of ordinary skill would have been motivated to do so as taught by Mo and to generate proliferating SCPs and examine the impact of NF1 mutations on Schwann cell lineage differentiation, as well as generate human neurofibromas (pg. 3 3rd para.) to serve as tractable platforms for drug identification and screening, as well as to provide unprecedented opportunities to elucidate the mechanisms underlying neurofibroma development and progression (pg. 3 3rd para.). One of ordinary skill would have specifically been motivated to make the combination because He teaches that the severely immunodeficient SD-RG rats support fast growth with rats as compared with mice (abstract), because the small size of mice limits the xenograft growth, sample collection, and drug evaluation (abstract), and because He specifically teaches and evidences that xenografts grow significantly faster and larger in SD-RG rats than in mouse models (abstract). Regarding the reasonable expectation of success, He evidences performing in a xenograft in the severely immunodeficient SD-RG (abstract; see also Methods pg. 141 col. 2), and Mo evidences implanting a xenograft population of human cells into the nervous system of an immunocompromised murine model (Methods pg. 17 last para.).
Regarding claim 1, concerning the limitation that the animal is “genetically engineered to be deficient in Cxcl10,” the rats of He are severely immunodeficient with an absence of mature T, B, and NK cells in the immune system as a result of the genetic mutations (abstract). Because CXCL10 is expressed by immune cells, the rat of He would have a deficiency in CXCL10 as claimed. Therefore, because the rat of He has been genetically engineered in a way which causes a reduction in CXCL10, it meets the structural limitations of instant claim.
Regarding the preamble “a humanized xenograft ” of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). Furthermore, the suggested murine model includes a murine subject that comprises human cells as a xenograft and therefore meets the broadest reasonable interpretation of a “humanized xenograft” murine model.
Regarding claim 3, as stated above, He teaches the murine model has a homozygous mutation in Rag1 (Rag1-/-; abstract; Results pg. 142 col. 2 “Generation of Rag1, Rag2, and Il2rg knockout rats by CRISPR/Cas9”).
Regarding claims 4, 7 and 10, further to the discussion of above, as stated above (see claim 1 rejection above), the population of cells suggested by Mo includes hiPSCs with a c.2041 C >T or c.6513T > A mutation (instant claims 4, 7 and 10) in NF1 (pg. 16 2nd para.), and Mo teaches the cells include proliferating SCPs (Schwann cell precursors) which are a type of (hiPSCs)-derived neuroglial progenitor cells (iNPCs) and include the mutation in NF1 (instant claim 7) (“biallelic Nf1 inactivation in early Schwann cell precursors” pg. 3; see also Results “Differentiation of isogenic hiPSCs harboring patient NF1 mutations directly into SCPs” pg. 3-4).
Regarding claim 13, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), He teaches the murine model is a rat model (Sprague Dawley (SD) rats); pg. 41 col. 1 Methods “Animals”).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 1, 3, and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over He et al. (FASEB J. 2019 Jan;33(1):140-150. Epub 2018 Jun 26.; henceforth “He”) in view of Hoffman et al. ( iScience. 2020 Jan 24;23(1):100813.; see IDS filed 14th, February, 2021; henceforth “Hoffman”).
Regarding claim 1, He discloses a humanized xenograft murine model comprising:
A murine subject (Sprague Dawley (SD) rats);
wherein the murine subject is genetically engineered to be deficient in Cxcl10 (“We knocked out Rag1, Rag2, and Il2rg” abstract; see also Methods pg. 141 col. 2)
However, regarding claim 1, although He teaches the severely immunodeficient SD-RG rats support fast growth of patient derived xenografts as compared with mice, thus holding great potential to serve as a newmodel for oncology research (abstract), He is silent to including a xenograft, a population of human cells, in the nervous system of the animal.
Nevertheless, regarding claim 1, Hoffman teaches implanting a population of human cells (human GBM cell line Results pg. 3) in the nervous system of a murine model to develop an in vivo human brain tumor engraftment model (pg. 1 last para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the xenograft murine model of He, and combine the known prior art element of the implant of human glioblastoma cells of He to obtain the predictable result of a xenograft model. One of ordinary skill would have been motivated to do so as taught by Hoffman to develop an in vivo human brain tumor engraftment model (pg. 1 last para.). One of ordinary skill would have specifically been motivated to make the combination because He teaches that the severely immunodeficient SD-RG rats support fast growth with rats as compared with mice (abstract), because the small size of mice limits the xenograft growth, sample collection, and drug evaluation (abstract), and because He specifically teaches and evidences that xenografts grow significantly faster and larger in SD-RG rats than in mouse models (abstract). Regarding the reasonable expectation of success, He evidences performing in a xenograft in the severely immunodeficient SD-RG (abstract; see also Methods pg. 141 col. 2), and Hoffman evidences implanting a xenograft population of human cells into the nervous system of a murine model (Figure 1).
Regarding claim 1, concerning the limitation that the animal is “genetically engineered to be deficient in Cxcl10,” the rats of He are severely immunodeficient with an absence of mature T, B, and NK cells in the immune system as a result of the genetic mutations (abstract). Because CXCL10 is expressed by immune cells, the rat of He would have a deficiency in CXCL10 as claimed. Therefore, because the rat of He has been genetically engineered in a way which causes a reduction in CXCL10, it meets the structural limitations of instant claim.
Regarding the preamble “a humanized xenograft ” of claim 1, the preamble merely states, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). Furthermore, the suggested murine model includes a murine subject that comprises human cells as a xenograft and therefore meets the broadest reasonable interpretation of a “humanized xenograft” murine model.
Regarding claim 3, as stated above, He teaches the murine model has a homozygous mutation in Rag1 (Rag1-/-; abstract; Results pg. 142 col. 2 “Generation of Rag1, Rag2, and Il2rg knockout rats by CRISPR/Cas9”).
Regarding claim 11, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), Hoffman teaches and makes obvious implanting a xenograft of human GBM cells. Hoffman specifically teaches performing the implant in murine brains (Figure 2. This xenograft as suggested by Hoffman falls under the broadest reasonable interpretation of a glioma like lesion because it is a tumor of glioma cells in the brain of an animal (See Figures 2-3).
Regarding claim 12, further to the discussion of claims 1 and 11 above, the glioma cells implant of Hoffman appears to be well-circumscribed (see Figure 2A) and therefore it would be obvious that the suggested in the rats of He would also be well-circumscribed.
Regarding claim 13, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), He teaches the murine model is a rat model (Sprague Dawley (SD) rats); pg. 41 col. 1 Methods “Animals”).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
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.
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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