DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/20/2026 has been entered.
Applicant’s amendments to the claims and arguments filed on April 20, 2026 have been received and entered. Claims 1-5, 7, 9 and 10 has been amended, while claim 6 has been canceled. It is noted that applicant response to previous office action is a non-responsive amendments as withdrawn claims 11-20 are not listed as part of claim listing. Applicant should correct the status of pending claim in response to this office action. For the sake of compact prosecution claim 11-20 are interpreted as withdrawn. Claims 1-5, 7-20 are pending.
Election/Restrictions
Applicant’s election of claims 1-10 (group I) in the reply filed on March 5, 2025 was acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant’s election of species (ii), causing calcific AS by TGFb1 hyperactivation predominantly in the at least one transgenic mouse mediated by increased activation of SMAD2, SMADS, SMADISU/5/9 and p38 MAPK;and decreased activation of pERK 1/2 MAPK signaling pathways as set forth in claim 7 is acknowledged. Upon further consideration, species set forth in claim 6 is hereby rejoined with the elected species as set forth in claim 7. Claim 8 reads on non-elected species and therefore is withdrawn from consideration.
Claims 8, 11-20 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 5, 2025.
Priority
This application is a 371 of PCT/US2020/058148 filed on 10/30/2020, which claims priority from a US provisional 62/954,884 filed on 12/30/2019.
Claims 1-5, 7, 9 and 10 are under consideration.
Claim Rejections - 35 USC § 112
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 1-5, 7-10 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.
Regarding claim 1, recitation of phrase mouse develops “age appropriate” aortic valve calcification is vague and indefinite because it is unclear as the phrase “age appropriate” is relative to what age or compared to which development group or control group? It is unclear if the phase means normal for its age or something else. The meets and bounds of the phrase “age appropriate” could not be ascertained. Claims 2-5, 7-10 are included in the rejection because they directly or indirectly depend from the rejected base claim.
New-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.
Claims 1-5, 7, 9 and 10 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. In the instant case, the recitation of limitation :”without requiring dietary or pharmacological trigger“ (claim 1) and “.mouse is born with three aortic valve leaflets wherein right and left coronary cusps of an aortic valve fuse at a base and form a raphe as the at least one Tgfb1TG; PostnCre mouse grows around 8 months of age” (claim 4) are considered new matter. Upon further review of the instant specification, examiner could not find support for what is encompassed by the negative limitation of not requiring dietary or pharmacological trigger or a mouse forming a raphe as the at least one Tgfb1TG; Postn Cre mouse grows around 8 months of age. There is no explicit or implicit support for formation of a raphe as mouse of the invention grows around 8 months of age or not requiring a pharmacological trigger. The specification at best in fig. 12 and 16 shows histopathology analysis of the raphe formation in Tgfb1TG;PostnCre mice but there is no disclosure of formation of a raphe as mouse of the invention grows around 8 months of age. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of mouse is born with three aortic valve leaflets wherein right and left coronary cusps of an aortic valve fuse at a base and form a raphe as the at least one Tgfb1TG; PostnCre mouse grows around 8 months of age or negative limitation, as claimed. In case if applicants have evidence to support otherwise, applicants are invited to indicate page and line number for the written support specifically for the negative limitation of claim 1 and right and left coronary cusps of an aortic valve fuse at a base and form a raphe as the at least one Tgfb1TG; PostnCre mouse grows around 8 months of age as recited in claim 4 of the instant application. MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). This is a new matter rejection.
Maintained & new -Claim Rejections - 35 USC § 112-in modified form
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 1-5, 7, 9 and 10 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 transgenic TGF beta1 +/+, Postn Cre male mouse whose genome comprises a nucleic acid encoding bioactive TGF beta 1, wherein said mouse overexpresses bioactive TGF beta 1 predominantly in the cardiac outflow tract endocardial cushion cells and adult valve interstitial cell, wherein the transgenic TGF beta1 +/+, Postn Cre mouse is produced by: crossing (i) a female mouse whose genome comprises CAG promoter driving expression of a loxP-flanked EGFP/polyA cassette upstream of a constitutively active HA tagged porcine transforming growth factor, beta 1 (Tgfb1) cDNA encoding polypeptide consisting of amino acid of SEQ ID NO: 2 , with (ii) a transgenic male mouse whose genome comprises a nucleic acid encoding Cre recombinase under the control of Postn promoter, wherein said TGF beta1 +/+, Postn Cre mouse is born with three aortic valve leaflets wherein right and left coronary cusps of an aortic valve fuse at a base and form a raphe as the mouse grows;
does not reasonably provide enablement for a model comprising at least one transgenic Tgfb1TF Postn Cre female mouse that develops age appropriate aortic valve calcification and calcific aortic valve stenosis or a female mouse is born with three aortic valve leaflets wherein right and left coronary cusps of an aortic valve fuse at a base and form a raphe as the at least one Tgfb1TG; PostnCre mouse grows around 8 months of age or using a TGFb1 cDNA that has been mutated in any way to prevent assembly of at least one latent associated peptide a broadly claimed. 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.
Applicant disagree with the rejection arguing instant application describes the specific phenotypes now claimed. The disclosure reports that the Tgfb1TG; PostnCre mice develop spontaneous, age-progressive aortic valve calcification and calcific aortic valve stenosis; that the mice are born with tri-leaflet valves; and that the right and left coronary cusps later fuse at the base to form a raphe as the animals age. The application further explains that this cusp fusion is an acquired phenotype rather than a congenital malformation. For Claim 7, the disclosure identifies increased activation of SMAD2. Claims 1, 2, 4, 5, 7, 9, and 10 are tied to the specific Tgfb1TG; PostnCre mouse model that the application actually teaches in detail. Claim 3, when read in the context of Claim 1, is likewise directed to the mutated Tgfb1 cDNA of that disclosed model. The law does not require the specification to enable undisclosed, unclaimed alternatives that the Office Action has imported into the rejection. Nor does the law require separate instructions for every possible embodiment where the claim is directed to a specific, concrete implementation that has been fully described and actually reduced to practice in the disclosure. Applicant continue to argue Claim 1 recites the very specific transgenic PostnCre-based mouse that develops age-appropriate aortic valve calcification and calcific aortic valve stenosis. The dependent claims narrow the scope even further by reciting no- additional-insult operation, the tri-leaflet-to-raphe progression, the acquired nature of the cusp fusion, the pathway signature, and the aortic valve stenosis phenotypes. Those narrower claims are necessarily enabled if the independent claim is enabled, and here the disclosure supports them directly. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant’s argument that claims recites the very specific transgenic PostnCre-based mouse that develops age-appropriate aortic valve calcification , it is noted that claims are broadly drawn to a mouse model comprising: at least one transgenic Tgfb1TG; PostnCre mouse bred from a Tgfb1Tg female mouse and a Peri CreTg,+ male mouse , wherein the at least one transgenic Tgfb1TG; PostnCre mouse overexpresses bioactive TGFB1 predominantly in cardiac outflow tract endocardial cushion cells and adult valve interstitial cells; and wherein the at least one transgenic Tgfb1TG: PostnCre mouse develops age appropriate aortic valve calcification and calcific aortic valve stenosis without requiring dietary or pharmacological triggers.
Thus, claim 1 as amended read on a mouse model comprising: at least one transgenic Tgfb1TG; PostnCre mouse produce by a process of breeding two mouse of distinct genotype. It is emphasized that breeding Tgfb1Tg female mouse and a Peri CreTg + male mouse would yield a mixed population of male and female mouse of different genotype including at least one Tgfb1TG; PostnCre mouse. As stated in previous office action the term mouse model is interpreted as a representation of a human disease or syndrome. The independent claims recite a mouse that does not require aTGFb1 allele that is driving expression of a loxP-flanked cassette upstream of a constitutively active porcine transforming growth factor, beta 1 (Tgfb1) cDNA encoding polypeptide consisting of amino acid of SEQ ID NO: 2. It is Cre-mediated recombination of the 'floxed' alleles that occurs exclusively in the tissue targeted by the (Peri) promoter, driving spatial expression/overexpression of Tgfb1 and therefore Cre transgene in the mouse may be irrelevant unless the aTGFb1 cassette is designed to respond to Cre. It is emphasized that resulting breeding of mouse of claim 3 would be enabling to the extent only the double positive offspring (TGFb1 and Cre) would be expected to express TGFb1 in the VIC as required by the claim in about only 25% of the population (bout 12.5% male and 12.5% female). In this situation not all the progeny of the animal following breeding could be considered as a model mouse. It is further emphasized that breeding a female homozygous for the TGFb1 allele and a male homozygous for the Cre transgene would yield progeny that would inherit both allele and all the resulting offspring could serve as disease model. In the instant case, claims 1 Tgfbl transgene expression requires Cre-mediated deletion of an intervening floxed enhanced green fluorescent protein (EGFP) gene in order for a ubiquitous B-actin promoter to transcribe constitutively active HA tagged Tgf 1 cDNA. However, none of the claims 1-2, 5, 7, 9 and 10 require aTGF-b1 expression is dependent on the recombination of loxP sites within the construct. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
In response to applicant’s argument that law does not require the specification to enable undisclosed, unclaimed alternatives that the Office Action has imported into the rejection, it should be noted that previous office action explicit reported that instant specification teaches mouse model that overexpresses bioactive TGFb1. Dependent claims limit the TGFb1 cDNA of the mouse that has been mutated to prevent assembly of at least one associate protein. The DNA sequences of all the TGFb1 cDNA that has been mutated to prevent assembly of at least one associate protein, other than the cysteine residues that is located in the pro region of the (TGF-β1 precursor at amino acid positions 223, and 225 to serine residue, encompassed within the plurality of TGFb1 cDNA of the mouse that has been mutated to prevent assembly of at least one associate protein have not been disclosed. The art teaches wild type TGGb1 is secreted as latent TGFb1 and downstream signaling would depend how fast the latent form is activated in the tissue. The guidance provided in the specification explicitly shows that the resulting phenotype of the mouse is dependent on sex (male vs female) and extent of TGFB1 expression in VIC of the mouse. Based upon the prior art there is expected to be sequence variation among the species of DNA sequences of other mutation to prevent assembly of one associated protein. Samuel et al (The EMBO Journal, 11, 4, 1599 - 1605, 1992, art of record) reported TGF-b1 is released by platelets as a latent high molecular weight complex. Activation of rTGF-b1 can be achieved by acidification. Both TGF-b1 and TGFb1 S33 were >90% biologically inactive prior to acidification, whereas TGF-b1S223 and TGF-b1S225 were 280% inactive. However, TGFb1S223/225 was at least 70% active without acid treatment, and in separate experiments (data not shown) levels of activity before and after acidification were equal. This suggests that the pro region of the TGF-b1 precursor is necessary to confer latency of rTGF-b1 (see page 13663, col. 1, para. 3). The specification has provided the description of TGFb1 as set forth in SEQ ID NO: 1 that could be changed to TGFb1 sequence as set forth in SEQ ID NO: 2 via changing Cysteine at 223 and 225 to Serine (see page 4 and 5 of the specification). The specification however has not disclosed the sequences of any of the other TGFb1 cDNA that has been mutated to prevent assembly of at least one associate protein as embraced by the claims. There is no evidence on the record of a relationship between the structures of the DNA molecules as set forth in SEQ ID NO: 2 provide any reliable information about the structure of DNA molecules within the genus of other mutation in TGFb1 to prevent assembly of at least one associate protein. In the instant case, neither prior art nor instant specification teaches latent TGFb1 overexpression would predictably produce the same phenotype as observed with active TGFb1. This is because activation of latent TGFb1 is known to be highly regulated and tissue dependent. In this regard, Stockis et al (Mol. BioSyst., 2017, 13, 1925--1935 ) teaches “only a few cell types activate TGF-b1, in response to specific stimuli and via mechanisms that are cell type specific” (see page 1926, col. 2, para. 2). The specification teaches that the model with fusion of the right and left coronary cusps (Type 1) is observed in males as commonly observed in human BAVs. However, the raphe formation and calcific AS progression seen in males is not observed in females is being currently investigated (see 159 of the published application) (emphasis added). This is further evident from the teaching of Al-Sammarraie, N. (Fall 2019Doctoral dissertation). Retrieved from https://scholarcommons.sc. edu/etd/5539, art of record ) who reported only one of transgenic female mice developed partial left and right coronary leaflets fusion with very short raphe, while none of the female mice developed aortic stenosis (Figure 2.20) as required by the claims. Therefore, claims are enabling for only TGF beta1 +/+, Postn Cre+/+ male mouse that develops aortic valve calcification and calcific aortic valve stenosis as required by the claims. Given such species differences in the expression of a constitutively active TGFb1 particularly when taken with the lack of guidance in the specification for the broader embodiments, it would have required undue experimentation to the levels of the transgene product, the consequences of that product, and therefore, the resulting phenotype. The specification fails to provide teachings or specific guidance to overcome the above-described unpredictability, in order to successfully to make and use the mouse with a specific phenotype, without reasonable expectation of success.
Withdrawn -Claim Rejections - 35 USC § 102
Claims 1-5, 7, 9 and 10 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Al-Sammarraie, N. (Fall 2019). Tissue-Specific Roles of Transforming Growth Factor Beta Ligands in Cardiac Outflow Tract Malformations and Calcific Aortic Valve Disease. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5539) as evidenced by Hall et al (Laboratory Investigation (2010) 90, 543–555). The declaration under 37 CFR 1.132 filed April 202, 2026 is sufficient to overcome the rejection of claims 1-5, 7, 9 and 10 based upon 102 (a)(1). Applicant’s submission of Azhar’s declaration pursuant to 37 C.F.R. § 1.130 disqualified Sammarraie, as prior art as claimed subject matter is directly or indirectly obtained from the inventor.
Withdrawn- Claim Rejections - 35 USC § 103
Claims 1-3, 6 and 7 remain rejected under 35 U.S.C. 103 as being unpatentable over Dutta et al (Curr Cardiol Rep (2018) 20: 21, 1-13) as evidenced by Jian et al (The Annals of Thoracic Surgery, 2003, 75, 457-465), Hall et al (Laboratory Investigation (2010) 90, 543–555), Gomez-Stallons et al (Arterioscl, Thrombosis and Vascular Biology, 2016, 36, 1396-1405) as evidenced by Shi (Cell, 2003 113(6), 685-700). Applicant’s argument that none of the mouse of prior art teach or suggest a Tgfb1TG; PostnCre mouse that develops age-appropriate aortic valve calcification and calcific aortic valve stenosis, is found persuasive, therefore, previous rejection of claims are hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Conclusion
No claims allowed.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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