DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-22, 26, 34, 36-69, 71-74, 76, 77, 79, 80 have been canceled. Claims 83-96 have been added. Claims 23-25, 27-33, 35, 70, 75, 78, 81-96 are pending.
Election/Restrictions
Applicant's election with traverse of Group I, claims 23-25, 27-33, 35, 70, 75, 78, 81-96 in the reply filed on 6-10-26 is acknowledged. The traversal is on the ground(s) that WO 2001079283 did not teach a mouse expressing CRBN. This is not found persuasive because Ebert (WO 2015/077058) taught a “transgenic [mouse or] knock-in mouse comprising a polynucleotide encoding a human CRBN polypeptide” (claim 31).
Applicants elected eRF3a as the CAP protein.
Claims 23-25, 27-33, 35, 70, 75, 78, 81-96 are under consideration as they related to measuring eRF3a expression in a mouse that expresses human CRBN.
Claim objections
Claim 23 is missing the step of administering the compound. It is also wholly unclear how the amount of the compound is being “optimized” for “amounts” or “schedules” because the claim is missing any features of the compound or the mouse that are being optimized. The claim is missing the structures/function of the genetic modification in the mouse. The claim can be written more accurately and succinctly as ---A method of screening compounds, the method comprising:
a) administering a compound to a genetically modified mouse whose genome comprises a nucleic acid sequence encoding human cerblon (CRBN) that expresses human CRBN;
b) measuring the amount of eRF3a expressed in the mouse obtained in step a)---, but it is wholly unclear what features of the compound or mouse are being screened beyond measuring the amount of eRF3a expressed in the mouse.
Claim 24 has a product-by-process embedded into a method claim. This makes the claim confusing.
Claim 28 does not result in any evaluation of a compound other than its effect on eRF3a expression. Claim 28 is objected to for reasons set forth above.
Claim 29 has a product-by-process embedded into a method claim. This makes the claim confusing.
Claim 31 does not result in any evaluation of a combination of compounds other than its effect on eRF3a expression. Claim 31 is objected to for reasons set forth above.
Claim 32 has a product-by-process embedded into a method claim. This makes the claim confusing.
Claim Rejections - 35 USC § 112
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.
Enablement
Claims 23-25, 27-33, 35, 70, 75, 78, 81-96 are 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 transgenic mouse whose genome comprises a nucleic acid sequence encoding a human cereblon (CRBN), does not reasonably provide enablement for a transgenic mouse expressing a human CRBN or fragment thereof or using the amount of eRF3a or any other CRBN-associated protein (CAP) expression in the mouse to screen compounds or make any assessment about their “dosing amounts” or “schedules”. 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/or use the invention commensurate in scope with these claims.
The specification does not making/using any mouse as broadly encompassed by claims 23, 28, 31 other than a transgenic mouse whose genome comprises a replacement of exon 2 but not exon 1 of an endogenous cereblon (CRBN) gene with an exogenous sequence consisting of cDNA encoding a human CRBN fragment having the nucleic acid sequence of SEQ ID NO: 7 and a polyadenylation sequence, wherein the mouse functionally expresses human CRBN isoforms 1 and 2.
Claim 23 is drawn to a method for optimizing dosing amounts and/or dosing schedules of a compound, comprising:
a) measuring the level of a biomarker in [[the]]a sample from a transgenic mouse expressing a human cereblon (CRBN) or a fragmentthereof, wherein the transgenic mouse has been administered the compound; and
b) adjusting the dosing amount and/or dosing schedule of the compound based on the level of the biomarker; wherein the biomarker is a CRBN-associated protein (CAP).
Claim 28 is drawn to evaluating the effect of a compound, the method comprising: a) measuring the level of a biomarker in [[the]] a sample from a transgenic mouse expressing a human CRBN or a fragment thereof, wherein the transgenic mouse has been administered the compound; and (b) comparing the level of the biomarker with a base level of the biomarker;wherein the biomarker is a CAP.
Claim 31 is drawn to evaluating the effect of a combination of compounds.
Claims 23, 28, 31 encompass using a mouse with a wild-type or inactivated endogenous CRBN gene.
The phenotype of mice with inactivated gene was unpredictable. Doyle (Transgenic Res., 2012, Vol. 21, pg 327-349) taught: “The generation of knockout mice has also revealed that many genetic functions in mammals are redundant and the targeted loss of genes that were thought to be critical sometimes had little to no effect (e.g., Joyner 1991). Although the redundancy of gene function added complexities not predictable on first principles, this phenomenon has often revealed previously unknown and/or underappreciated molecular/cellular pathways that possibly represent new targets for therapeutic intervention. Some studies involving knockout mice have even demonstrated significant differences between mice (i.e., rodents) and humans (i.e., primates). For example, whereas the loss of the CFTR gene in humans is specifically linked to the pulmonary pathophysiological changes of cystic fibrosis (Riordan 1989), mice carrying a similar null mutation display virtually no lung phenotype (Snouwaert 1992). Such studies, while frustrating and seemingly unproductive with regard to modeling human diseases, serve as insightful investigations that attest to the complexity of mammalian biochemistry/ physiology and a cautionary note to investigators using mice to model human disease.”
The precise reagents required for knocking in and humanizing a mouse gene are unpredictable as evidenced by Saito (Nature Neuroscience, May 2014, Vol. 17, No. 5, pg 661-663) who taught that when attempting to humanize the APP gene in mice, they determined intron 16 was indispensable for correct expression of APP. Saito also confirms the unpredictability of incorporating two mutations together would “potentially exert unexpected effects” (pg 661, col. 1, 2nd full paragraph).
Chan (2006/0179501) taught making mice expressing human CD20. Previous attempts of expressing CD20 in mice were not successful because of control regions in the transgene construct (sentence bridging col. 1-2 on pg 12). Chan did not teach the control region used to successfully express a human CD protein in transgenic mice. Therefore, Chan confirms the unpredictability of functionally expressing a human protein in transgenic mice.
The phenotype of humanized transgenic rodents was unpredictable as evidenced by Garanto (PLoS, Nov. 2013, Vol. 8, No. 11, e79369, pg 1-10) who taught humanized transgenic mice had unexpected mRNA splicing in an humanized CEP290 gene.
Pg 2, para 7; pg 3, para 8; pg 4, para 9; pg 5, para 10, et al. teaches: “In certain embodiments, the nucleic acid sequence encodes a fragment of human CRBN that comprises a polypeptide that starts at codon 24 Glutamate of human CRBN isoform 1 and ends at the last codon of human CRBN isoform 1. In other embodiments, the nucleic acid sequence encodes a fragment of human CRBN that comprises a polypeptide that starts at codon 23 Glutamate of human CRBN isoform 2 and ends at the last codon of human CRBN isoform 2.”
Fig. 2A-D (pg 18, para 47) describes a targeting design for knocking in human CRBN into a mouse genome. The targeting construct (Fig. 2B) contains part of the human CRBN cDNA starting from codon 24 of human CRBN isoform 1, bGF pA, and a neo cassette flanked by two loxP sites. Fig. 2C generically describes the targeted genome after human CRBN knock-in; the exogenous sequence encoding human CRBN replaces exon 2 of the endogenous mouse CRBN gene. The specific structure of the human CRBN sequence is not disclosed. While the specification contemplates the human CRBN cDNA may be of any length, it is unclear whether applicants simply replaced exon 2 of the endogenous CRBN gene with exon 2 of human isoform 1 or if applicants introduced the entire coding region for human CRBN isoform 1.
Fig. 3 generically shows where homology arms would go in a vector for homologous recombination but does not teach the structure or nucleic acid sequence of the homology arms or the target sequence within the endogenous mouse CRBN gene. Fig. 3A clarifies that the human cDNA begins at codon 24, glutamate, [of human CRBN isoform 1?] and ends at the stop codon (pg 18, para 49).
Paragraphs 153 and 289 discuss the strategy for making a knock-in vector for homologous recombination of the human cDNA into the endogenous gene, but they do not teach the structure or nucleic acid sequence of the homology arms or the target sequence within the endogenous CRBN gene. The specification does not teach any other target sequence or gene for targeting. The specification does not teach the nucleic acid sequence of any homology arms, specifically those required to replace exon 2 of the endogenous CRBN gene with human cDNA as suggested in Fig. 2C that would allow precise integration of the human cDNA.
The specification does not enable using any “fragment” of a human CRBN or using a fragment of a nucleic acid encoding human CRBN as encompassed by claims 23, 28, 31. The specification does not teach how to use a fragment of human CRBN that is non-functional, that is a single nucleotide, that is an oligonucleotide, etc. The specification is limited to a fragment of a “nucleic acid encoding human CRBN” that starts at codon 23 or 24 of the human CRBN protein and ends at the stop codon (claims 5 and 6). The specification does not teach how use a mouse expressing a fragment of human CRBN that is non-functional, that is a single nucleotide, that is an oligonucleotide, etc.
The specification does not enable expressing full length human CRBN as encompassed by claims 23, 28, 31. The specification does not teach how to express functional chimeric mouse-human CRBN as shown in Fig. 2 when the human portion is full length as required in claim 23, 28, 31. The specification does not teach how to inactivate the entire endogenous CRBN coding region so that the entire human CRBN coding region will be functionally inserted into the genome and expressed. The specification does not correlate homologous recombination strategies for targeting the endogenous CRBN gene to any other homologous recombination strategies or basic transgenesis that causes integration of the human cDNA into the genome. Without such guidance, it would have required those of skill undue experimentation to determine how to express full length human CRBN in a mouse as required in claim 23, 28, 31.
The specification does not enable making and/or using a mouse with any mouse-human chimeric CRBN gene as encompassed by claims 23, 28, 31 for reasons set forth above, specifically as it relates to making a mouse-human chimeric CRBN gene comprising codon 23 or 24 to the stop codon of human CRBN isoform 1 or 2.
The specification does not enable using mice expressing human CRBN to screen compounds as required in claims 23, 28, 31 in any meaningful way. The claims are missing the step of administering the compound. It is unclear how the amount of the compound is being “optimized” for “amounts” or “schedules” because the claim is missing any features of the compound or the mouse that are being optimized. It is wholly unclear what features of the compound or mouse are being screened beyond measuring the amount of eRF3a expressed in the mouse. The specification does not correlate eRF3a or any other “CAP” expression in the mouse to anything meaningful about a compound administered to the mouse. Claim 25 requires making adjustments based on the expression of eRF3a, but the specification is completely silent about when/why to make such adjustments based on eRF3a expression. Claims 30 and 33 set the controls for the “base level of the biomarker” but it is unclear when/why any difference in eRF3a expression would provide any information about the compound administered to the mouse. Claims 35, 75, 78, 90-94 set forth various specific compounds, but it is unclear how eRF3a expression in a mouse that expresses human CRBN reveals anything about their dosage amounts or “scheduling”. Claim 81 requires the method is for evaluating the effect of the compound on antigen-specific T-cell killing; however, it is unclear how such an analysis has anything to do with eRF3a expression or how it would provide any information about the compound or its dosing amount or schedule. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to use the method of claim 23, 28, or 31 to screen compounds or make any decisions about them regarding their “dosing amounts” or “schedules”.
The specification does not enable making and/or using a mouse with human CRBN controlled by a homologous mouse promoter as required in claims 84, 86, 88 for reasons set forth above.
Written Description
Claims 23-25, 27-33, 35, 70, 75, 78, 81-96 are 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 claim(s) contains 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 23, 28, 31 and their breadth are described above.
The state of the art and the teachings in the specification are discussed above.
The specification lacks written description for using any “fragment” of a human CRBN or using a fragment of a nucleic acid encoding human CRBN as encompassed by claims 23, 28, 31. The specification does not teach how to use a fragment of human CRBN that is non-functional, that is a single nucleotide, that is an oligonucleotide, etc. The specification is limited to a fragment of a “nucleic acid encoding human CRBN” that starts at codon 23 or 24 of the human CRBN protein and ends at the stop codon (claims 5 and 6). The specification does not teach how use a mouse expressing a fragment of human CRBN that is non-functional, that is a single nucleotide, that is an oligonucleotide, etc.
The specification lacks written description for expressing full length human CRBN as encompassed by claims 23, 28, 31. The specification does not teach how to express functional chimeric mouse-human CRBN as shown in Fig. 2 when the human portion is full length as required in claim 23, 28, 31. The specification does not teach how to inactivate the entire endogenous CRBN coding region so that the entire human CRBN coding region will be functionally inserted into the genome and expressed. The specification does not correlate homologous recombination strategies for targeting the endogenous CRBN gene to any other homologous recombination strategies or basic transgenesis that causes integration of the human cDNA into the genome.
The specification lacks written description for a mouse with any mouse-human chimeric CRBN gene as encompassed by claims 23, 28, 31 for reasons set forth above, specifically as it relates to making a mouse-human chimeric CRBN gene comprising codon 23 or 24 to the stop codon of human CRBN isoform 1 or 2.
The specification lacks written description for mice expressing human CRBN to screen compounds as required in claims 23, 28, 31 in any meaningful way. The claims are missing the step of administering the compound. It is unclear how the amount of the compound is being “optimized” for “amounts” or “schedules” because the claim is missing any features of the compound or the mouse that are being optimized. It is wholly unclear what features of the compound or mouse are being screened beyond measuring the amount of eRF3a expressed in the mouse. The specification does not correlate eRF3a or any other “CAP” expression in the mouse to anything meaningful about a compound administered to the mouse. Claim 25 requires making adjustments based on the expression of eRF3a, but the specification is completely silent about when/why to make such adjustments based on eRF3a expression. Claims 30 and 33 set the controls for the “base level of the biomarker” but it is unclear when/why any difference in eRF3a expression would provide any information about the compound administered to the mouse. Claims 35, 75, 78, 90-94 set forth various specific compounds, but it is unclear how eRF3a expression in a mouse that expresses human CRBN reveals anything about their dosage amounts or “scheduling”. Claim 81 requires the method is for evaluating the effect of the compound on antigen-specific T-cell killing; however, it is unclear how such an analysis has anything to do with eRF3a expression or how it would provide any information about the compound or its dosing amount or schedule.
The specification lacks written description for using a mouse with human CRBN controlled by a homologous mouse promoter as required in claims 84, 86, 88 for reasons set forth above.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 23-25, 27-33, 35, 70, 75, 78, 81-96 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 23, 28, 31 are missing the step of administering the compound. It is also wholly unclear how the amount of the compound is being “optimized” for “amounts” or “schedules” because the claims are missing any features of the compound or the mouse that are being optimized. The claims are missing the structures/function of the genetic modification in the mouse. There is no nexus between any features of the compound or the mouse are being screened, the amount of eRF3a expressed in the mouse, and making any decisions about the compound, specifically its “dosing amount” or “schedule”.
Ebert (WO 2015/077058) taught a “transgenic [mouse or] knock-in mouse comprising a polynucleotide encoding a human CRBN polypeptide” (claim 31), but the art at the time of filing did not reasonably teach or suggest administering a compound to the mouse followed by measuring eEF3a expression in the mouse as required in claims 23, 28, 31.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Zhu (Nature Comm., 2019, Vol. 10, No: 1845, pg 1-13) described various knockin mice known in the art at the time of applicants’ filing date, including those with partial knockins:
Ramchandani (Mol. Physiol., 2011, Vol. 16, pg 809-817) described replacing an exon of the mouse OPRM1 gene with a human exon.
Albertelli (Mol. Endocrinology, 2006, Vol. 20, No. 6, pg 1248-1260) described replacing an exon of the mouse androgen receptor gene with a human exon.
Kitamoto (Biochemical and Biophysical Res. Comm., 1996, Vol. 222, pg 742-747) described replacing an exon of the mouse prion protein gene with a human exon.
Lute (Blood, 2005, Vol. 106, No. 9, pg 3127-3133) described replacing exons of the mouse CTLA4 gene with human exons.
Liu (7504554) described replacing exons of the mouse CTLA4 gene with human exons.
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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