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 1-8 have been canceled. Claims 9-13 have been added and are 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 1-26-26 have been fully considered but they are not persuasive.
Claim objections
Claims 9 and 10 should begin ---A transgenic mouse whose genome comprises: i)--- and can be written more clearly as ---i) a nucleic acid sequence encoding green fluorescent protein (GFP) flanked on both sides by loxP sites and operably linked to an actb promoter; and ii) an exogenous nucleic acid sequence encoding cofilin...---. The function of the genetic modification must also be clearly set forth.
Claim Rejections - 35 USC § 112
Written Description
Claims 9-13 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 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.
Withdrawn rejections
The rejection regarding making any species genetically modified multicellular organism as broadly encompassed by claims 1 and 5 has been withdrawn because claims 9 and 10 are limited to transgenic mice.
The rejection regarding modifying an endogenous PTGDS “locus” as required in claim 1 has been withdrawn in view of the amendment.
The rejection regarding “founders” having the structures/functions as broadly encompassed by claims 1 and 5 other than the two F0s in Fig. 2A has been withdrawn in view of the amendment and in favor of rejection A).
Pending rejections
The specification lacks written description for making any transgenic mouse “whose genome, comprising an Actb promoter operably linked to a first nucleic acid sequence encoding GFP flanked by loxP sites, and downward linked to Cofilin” in claim 9 or “whose genome, comprising an Actb promoter operably linked to a first nucleic acid sequence encoding GFP flanked by loxP sites, and downward linked to Cofilin, and a second nucleic acid sequence encoding a Cre-ERT2 fusion operably forward linked to a Pgkl promotor, wherein the first nucleic acid sequence encoding GFP is removable by tamoxifen” as required in claim 10 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).
Applicants point to Fig. 2A for support, but claims 9 and 10 encompass operably linking the nucleic acid sequence encoding GFP to a cofilin protein; claims 9 and 10 are missing the exogenous nucleic acid sequence encoding Cofilin. Claim 9 is missing the function of the sequence encoding GFP flanked by two loxP sites being capable of being removed by Cre recombinase. Claims 9 and 10 are missing the fact that the removal of the nucleic acid sequence encoding GFP by recombinase results in the nucleic acid sequence encoding cofilin being operably linked to the actb promoter.
The specification fails to teach how to make/use any transgenic mouse as broadly encompassed by claims 9 and 10 with inaccurate structures and missing function other than the mouse described in Fig. 2A as described in the paragraph above.
Accordingly, the specification lacks written description for any mouse as broadly encompassed by claim 9 or 10.
New rejection
B) The specification lacks written description for a transgenic mouse with “an aging mimicry phenotype” in claims 11-13. The metes and bounds of “aging mimicry phenotype” cannot be determined but encompasses death, wrinkling, slowness, muscle atrophy, senility, Alzheimer’s disease, dementia, slow metabolism, menopause, etc. Claim 12 says “aging mimicry 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 aging as claimed. In fact, it is unclear how to use a mouse the moves more at night than a wild-type mouse as a model of any disease condition. Claim 13 says “aging mimicry phenotype” is “enlarged lateral ventricle in the brain”; however, this is not necessarily a phenotype associated with aging and 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 of any disease condition. Accordingly, claims 11-13 lack written description.
Response to arguments
Applicants’ argue the amendment overcomes the rejections. Applicants’ argument is not persuasive for reasons set forth above.
Enablement
Claims 9-13 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 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.
Withdrawn rejections
The rejection regarding making any species genetically modified multicellular organism as broadly encompassed by claims 1 and 5 has been withdrawn because claims 9 and 10 are limited to transgenic mice.
The rejection regarding modifying an endogenous PTGDS “locus” as required in claim 1 has been withdrawn in view of the amendment.
The rejection regarding “founders” having the structures/functions as broadly encompassed by claims 1 and 5 other than the two F0s in Fig. 2A has been withdrawn in view of the amendment and in favor of rejection A).
Pending rejections
The specification does not enable making/using any transgenic mouse “whose genome, comprising an Actb promoter operably linked to a first nucleic acid sequence encoding GFP flanked by loxP sites, and downward linked to Cofilin” in claim 9 or “whose genome, comprising an Actb promoter operably linked to a first nucleic acid sequence encoding GFP flanked by loxP sites, and downward linked to Cofilin, and a second nucleic acid sequence encoding a Cre-ERT2 fusion operably forward linked to a Pgkl promotor, wherein the first nucleic acid sequence encoding GFP is removable by tamoxifen” as required in claim 10 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) .
Applicants point to Fig. 2A for support, but claims 9 and 10 encompass operably linking the nucleic acid sequence encoding GFP to a cofilin protein; claims 9 and 10 are missing the exogenous nucleic acid sequence encoding Cofilin. Claim 9 is missing the function of the sequence encoding GFP flanked by two loxP sites being capable of being removed by Cre recombinase. Claims 9 and 10 are missing the fact that the removal of the nucleic acid sequence encoding GFP by recombinase results in the nucleic acid sequence encoding cofilin being operably linked to the actb promoter.
The specification fails to teach how to make/use any transgenic mouse as broadly encompassed by claims 9 and 10 with inaccurate structures and missing function other than the mouse described in Fig. 2A as described in the paragraph above.
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 or 10.
New rejection
B) The specification does not enable making/using a transgenic mouse with “an aging mimicry phenotype” in claims 11-13. The metes and bounds of “aging mimicry phenotype” cannot be determined but encompasses death, wrinkling, slowness, muscle atrophy, senility, Alzheimer’s disease, dementia, slow metabolism, menopause, etc. Claim 12 says “aging mimicry 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 aging as claimed. In fact, it is unclear how to use a mouse the moves more at night than a wild-type mouse as a model of any disease condition. Claim 13 says “aging mimicry phenotype” is “enlarged lateral ventricle in the brain”; however, this is not necessarily a phenotype associated with aging and 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 of any disease condition. 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 claims 11-13.
Response to arguments
Applicants’ argue the amendment overcomes the rejections. Applicants’ argument is not persuasive for reasons set forth above.
Indefiniteness
Claims 9-13 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 9 is indefinite because it does not set forth the structure or function of the transgenic mouse. It says the nucleic acid sequence encoding GFP is “downward linked to cofilin”; however, cofilin is a protein and cannot be linked to a nucleic acid. The claim is missing the function of the sequence encoding GFP flanked by two loxP sites being capable of being removed by Cre recombinase. Claim 9 is missing the fact that the removal of the nucleic acid sequence encoding GFP by recombinase results in the nucleic acid sequence encoding cofilin being operably linked to the actb promoter.
Claim 10 is indefinite because it does not set forth the structure or function of the transgenic mouse. It says the nucleic acid sequence encoding GFP is “downward linked to cofilin”; however, cofilin is a protein and cannot be linked to a nucleic acid. Claim 10 is missing the fact that the removal of the nucleic acid sequence encoding GFP by recombinase results in the nucleic acid sequence encoding cofilin being operably linked to the actb promoter. 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 10 cannot be determined.
Claim 11 is indefinite because the metes and bounds of the phrase “aging mimicry phenotype” cannot be determined. encompasses death, wrinkling, slowness, muscle atrophy, senility, Alzheimer’s disease, dementia, slow metabolism, menopause, etc. Claim 12 says “aging mimicry 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 aging as claimed. In fact, it is unclear how to use a mouse the moves more at night than a wild-type mouse as a model of any disease condition. Claim 13 says “aging mimicry phenotype” is “enlarged lateral ventricle in the brain”; however, this is not a phenotype associated with aging 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 aging.
Claim 12 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 13 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
Claims 9-13 are 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). This is equivalent to the transgenic mice of claims 9 and 10.
Claim 11 has been included because the mice age which is an “aging phenotype mimicry”.
Claim 12 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.
Claim 13 has been included because the mice inherently MUST exhibit enlarged lateral ventricle in brain as compared to smaller mice or smaller rodents.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicants’ argue inducible, systemic expression of cofilin 1 allowed the mice to live which was unexpected. Applicants’ argument is not persuasive. The claim does not require the mouse survives, does not require the mouse is capable of inducing cofilin 1 expression, or that recombination causes systemic expression of cofilin 1.
Applicants argue the phenotype of “aging mimicry” was unexpected. Applicants’ argument is not persuasive because the metes and bounds of the concept are unclear, because all mice age which is “aging mimicry”, and because applicants results do not relate to increased risk of cancer, wrinkles, dementia, Parkinson’s disease, Alzheimer’s disease, macular degeneration, etc. as broadly encompassed by “aging mimicry”.
Conclusion
No claim is allowed.
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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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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