DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7-23-26 has been entered.
Claims 1-8, 10-13 have been canceled. Claim 9 is pending and under consideration.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Applicant's arguments filed 7-23-26 have been fully considered but they are not persuasive.
Claim objections
Claim 9 can be written more succinctly as ---A transgenic mouse whose genome comprises: i) a nucleic acid sequence encoding green fluorescent protein (GFP) flanked on both sides by loxP sites and operably linked to an actb promoter upstream from an exogenous nucleic acid sequence encoding cofilin; and a nucleic acid sequence encoding ERT2Cre recombinase...---. If there is something else in the Cre recombinase system, then it must be clearly set forth, e.g. a tamofoxin-specific element.
The function of the genetic modification in claim 1 can be written more clearly. Administration of tamoxifen to the mouse must be capable of inducing expression of the ERT2Cre, which must be capable of excising the nucleic acid sequence encoding GFP, which must cause the nucleic acid encoding cofilin 1 to become operably linked to the actb promoter; recombination must capable of causing cofilin 1 to become overexpressed in the mouse.
The phenotype of the mouse after the nucleic acid encoding cofilin 1 becomes operably linked to the actb promoter can be written more clearly, e.g. wherein the mouse is capable of exhibiting reduced activity at night and enlarged lateral ventricle of the brain as compared to prior to administering tamoxifen.
Claim Rejections - 35 USC § 112
Written Description
Claim 9 remains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A) The specification lacks written description for making any transgenic mouse comprising “a) a first transgene comprising:(i) an Actb promoter;(ii) a first nucleic acid sequence encoding a green fluorescent protein (GFP) flanked on both sides by loxP sites, wherein the first nucleic acid sequence is operably linked to the Actb promoter; and(iii) an exogenous second nucleic acid sequence encoding a cofilin-1 protein, wherein the exogenous second nucleic acid sequence is positioned downstream of the first nucleic acid sequence; and (b) a second transgene comprising an inducible Cre recombinase expression system encoding an ERT2Cre fusion protein; wherein, upon administration of tamoxifen to the mouse, the ERT2Cre fusion protein mediates excision of the first nucleic acid sequence encoding GFP, thereby positioning the exogenous second nucleic acid sequence encoding the cofilin-1 protein into operable linkage with the Actb promoter to drive over-expression of the cofilin-1 protein relative to a wild-type mouse; and wherein said over-expression of the cofilin-1 protein induces a circadian rhythm disruption phenotype characterized by a reduced activity level at night time and an enlarged lateral ventricle in the brain of the mouse” in claim 9 other than a genetically modified mouse whose genome comprises i) a nucleic acid sequence encoding a fluorescent protein flanked by two loxP sites operably linked to a promoter; ii) an exogenous nucleic acid sequence encoding a protein of interest; and iii) a nucleic acid sequence encoding a Cre-ERT2 fusion protein operably linked to a promoter.
The sequence encoding the fluorescent protein must be removable by recombinase, and the sequence encoding cofilin must be operably linked to the promoter after administration of tamoxifen and recombination (F1+TAM). The specification lacks written description for a mouse with any “inducible Cre recombinase system” encoding an ERT2Cre protein as required in claim 9. An inducible Cre recombinase system must be inducible by tamofoxin which is missing from item b) of claim 9. The structures associated with the “system” that allow it to be inducible by tamofoxin are missing from the claim, e.g. a tamofoxin-responsive element? Promoter? Accordingly, the specification lacks written description for any mouse as broadly encompassed by claim 9.
B) The specification lacks written description for a transgenic mouse with “a circadian rhythm disruption phenotype characterized by reduced activity level at night time and enlarged lateral ventricle in the brain” in claim 9. The metes and bounds of “a circadian rhythm disruption phenotype characterized by reduced activity level at night time and enlarged lateral ventricle in the brain” cannot be determined but encompasses reduced activity at night and enlarged lateral ventricle in the brain. Claim 9 says the “phenotype” is “reduced activity at night time”, but the metes and bounds of that are unclear because older mammals sleep less than younger mammals. Example 7 (pg 8) discusses movement of mice after overexpressing cofilin as compared to wild-type mice; however, it is unclear how this is associated with “circadian rhythm” as claimed. In fact, it is unclear how to use a mouse the moves less at night than a wild-type mouse as a “model” as required in the preamble, specifically of “circadian rhythm”. Claim 9 says “circadian rhythm phenotype” is “enlarged lateral ventricle in the brain”; however, this does not have anything to do with “circadian rhythm” because it can be a congenital condition. More importantly, it is unclear how to use a mouse with an enlarged lateral ventricle in the brain as a “model” as required in the preamble, specific of “circadian rhythm disorders”. Accordingly, claim 9 lack written description.
Response to arguments
Applicants’ argue the amendment overcomes the rejections. Applicants’ argument is not persuasive for reasons set forth above.
Enablement
Claim 9 remains 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 genetically modified mouse whose genome comprises A) a nucleic acid sequence encoding a fluorescent protein and a stop-cassette flanked by loxP sites operably linked to an ACTB promoter and nucleic acid sequence encoding Cofilin 1 (CFL1); and B) a nucleic acid sequence encoding Cre recombinase operably linked to PGK1 promoter, wherein the mouse does not express CFL1 in the absence of tamoxifen but does express CFL1 when treated with tamoxifen, does not reasonably provide enablement for the claims as written. 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/use the invention commensurate in scope with these claims.
A) The specification does not enable making any transgenic mouse as described in claim 9 other than a genetically modified mouse whose genome comprises i) a nucleic acid sequence encoding a fluorescent protein flanked by two loxP sites operably linked to a promoter; ii) an exogenous nucleic acid sequence encoding a protein of interest; and iii) a nucleic acid sequence encoding a Cre-ERT2 fusion protein operably linked to a promoter.
The sequence encoding the fluorescent protein must be removable by recombinase, and the sequence encoding cofilin must be operably linked to the promoter after administration of tamoxifen and recombination (F1+TAM). The specification lacks written description for a mouse with any “inducible Cre recombinase system” encoding an ERT2Cre protein as required in claim 9. An inducible Cre recombinase system must be inducible by tamofoxin which is missing from item b) of claim 9. The structures associated with the “system” that allow it to be inducible by tamofoxin are missing from the claim, e.g. a tamofoxin-responsive element? Promoter? 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 make/use any mouse as broadly encompassed by claim 9.
B) The specification does not enable making/using a transgenic mouse with “a circadian rhythm disruption phenotype characterized by reduced activity level at night time and enlarged lateral ventricle in the brain” in claim 9. The metes and bounds of “a circadian rhythm disruption phenotype characterized by reduced activity level at night time and enlarged lateral ventricle in the brain” cannot be determined but encompasses reduced activity at night and enlarged lateral ventricle in the brain. Claim 9 says the “phenotype” is “reduced activity at night time”, but the metes and bounds of that are unclear because older mammals sleep less than younger mammals. Example 7 (pg 8) discusses movement of mice after overexpressing cofilin as compared to wild-type mice; however, it is unclear how this is associated with “circadian rhythm” as claimed. In fact, it is unclear how to use a mouse the moves less at night than a wild-type mouse as a “model” as required in the preamble, specifically of “circadian rhythm”. Claim 9 says “circadian rhythm phenotype” is “enlarged lateral ventricle in the brain”; however, this does not have anything to do with “circadian rhythm” because it can be a congenital condition. More importantly, it is unclear how to use a mouse with an enlarged lateral ventricle in the brain as a “model” as required in the preamble, specific of “circadian rhythm disorders”. 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 make/use the mouse of claim 9 as a “model”, specifically of “circadian rhythm”.
Indefiniteness
Claim 9 remains 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 9 is indefinite because the metes and bounds of a “transgene comprsing an inducible Cre recombinase system encoding ERT2Cre” cannot be determined and is missing essential element. It does not set forth the genome of the mouse contains a nucleic acid sequence encoding ERT2Cre. The phrase does not capture the fact that there must be tamoxifen-responsive elements in the “system”. Perhaps there is a specific promoter required as well. Cre-ERT2 mice in claim 10 were known in the art as described by Ruzankina (Cell Stem Cell, 2007, Vol. 1, pg 113-126) (pg 114, col. 1 “Generation of Cre-ERT2 transgenic mice…”) who said “Cre-ERT2 is a fusion protein composed of Cre recombinase and a mutant form of the estrogen receptor that is selectively activated only in the presence of tamoxifen (TAM), but not estrogen (Feil et al., 1997). In combination with a flox-conditional allele of ATR (Brown and Baltimore, 2003), the Cre-ERT2 line provides a system to efficiently delete ATR both spatially and temporally in the mouse.” These elements and the function of the transgene are missing from the 2nd founder. See also Korecki (Genetics, 2019, Vol. 211, pg 1155-1177). Overall, the structures/functions of the transgenic mouse in claim 9 are missing essential elements.
Claim 9 is indefinite because the metes and bounds of the phrase “circadian rhythm phenotype” that is “reduced activity at night time” does not make sense because older mammals sleep less than younger mammals. Example 7 (pg 8) discusses movement of mice after overexpressing cofilin as compared to wild-type mice; however, it is unclear how this is associated with aging as claimed. In fact, it is unclear how to use a mouse the moves less at night than a wild-type mouse as a “model” as required in the preamble, specifically of “circadian rhythm” disorder. Claim 9 says “circadian rhythm phenotype” is “enlarged lateral ventricle in the brain”; however, this is not a phenotype associated with circadian rhythm and can be a congenital condition. Example 8 (pg 9) discusses brain images of the mice; however, it is unclear how the phenotype is associated with circadian rhythm.
Claim 9 is indefinite because it requires the mouse has “reduced activity at nighttime”, but the concept is meaningless without a comparison. It is unclear whether the activity is reduced over time, as compared to humans, as compared to a wild-type mouse, etc. Therefore, the concept is missing essential elements.
Claim 9 is indefinite because it requires the mouse has “enlarged lateral ventricle in brain”, but the concept is meaningless without a comparison. It is unclear whether the ventricle is enlarged over time, enlarged as compared to humans, enlarged as compared to a wild-type mouse, etc. Therefore, the concept is missing essential elements.
Response to arguments
Applicants’ argue the amendment overcomes the rejections. Applicants’ argument is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 103
Claim 9 remains rejected under 35 U.S.C. 103 as being unpatentable over Korecki (Genetics, 2019, Vol. 211, pg 1155-1177) in view of Bellenchi (Genes & Development, 2007, Vol. 21, pg 2347-2357).
Korecki taught a genetically modified mouse whose genome comprises A) a nucleic acid sequence encoding a GFP protein and a stop-cassette flanked by two loxP sites operably linked to a promoter and nucleic acid sequence encoding a protein of interest; and B) a nucleic acid sequence encoding a Cre recombinase-ERT2 fusion protein operably linked to promoter, wherein the mouse does not express protein of interest in the absence of tamoxifen but does express protein of interest when treated with tamoxifen (pg 1161, Fig. 1).
Korecki did not teach the protein of interest was cofilin 1 (CFL1) as required in claim 9 or 10.
However, targeting the CFL1 for research purposes was well-known as evidenced by Bellenchi (Supplement Fig. 1B).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make a genetically modified mouse whose genome comprises A) a nucleic acid sequence encoding a GFP protein and a stop-cassette flanked by loxP sites operably linked to a promoter and nucleic acid sequence encoding a protein of interest; and B) a nucleic acid sequence encoding a Cre recombinase-ERT2 fusion protein operably linked to promoter as described by Korecki wherein the protein of interest was CFL1 described by Bellenchi. Those of ordinary skill in the art at the time of filing would have been motivated to apply the “Stop-n-go” system of Korecki to the CFL1 coding sequence for temporal control of CFL1 expression in a tissue of interest (depending upon the promoter used for Cre-ERT2 expression). The “reduced activity” phenotype in claim 9 has been included because some mice inherently MUST exhibit reduced activity at nighttime as compared to other days. Over time, all animals MUST exhibit reduced activity at nighttime as compared to other days. The enlarged lateral ventricle phenotype in claim 9 has been included because the mice inherently MUST exhibit enlarged lateral ventricle in the brain as compared to smaller mice or smaller rodents.
Response to arguments
Applicants’ argue Bellenchi “teaches away” because it focuses on the loss of cofilin during brain development. Applicants argue there is no motivation to combine. Applicants’ arguments are not persuasive. Korecki taught overexpressing a protein of interest. Those of skill would have wanted to use CFL1 as the protein of interest investigate the role of CFL1 in tissues in vivo.
Applicants argue the phenotype of a “circadian rhythm” disorder of decreased activity and enlarged lateral ventricles was unexpected. Applicants’ argument is not persuasive because the metes and bounds of the concept are unclear. The “reduced activity” phenotype in claim 9 has been included because some mice inherently MUST exhibit reduced activity at nighttime as compared to other days. Over time, all animals MUST exhibit reduced activity at nighttime as compared to other days. The enlarged lateral ventricle phenotype in claim 9 has been included because the mice inherently MUST exhibit enlarged lateral ventricle in the brain as compared to smaller mice or smaller rodents.
Conclusion
No claim is allowed.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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