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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4, 7-9 and 14-17 in the reply filed on 8/28/2025 is acknowledged.
Claims 5, 6, 10-13 and 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8/28/2025.
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, 3, 4, 7-9 and 15-17 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.
When the claims are analyzed in light of the specification, the instant invention encompasses a nucleic acid molecule comprising any functional fragments from SEQ IDs: 1 or 2, any functional fragments from SEQ ID NO: 3 and any functional fragments from SEQ ID NO: 4, and which facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
SEQ ID NO: 1 is drawn to the mouse transthyretin promoter (204 bp).
SEQ ID NO: 2 is drawn to the minimal mouse transthyretin promoter (152 bp).
SEQ ID NO: 3 is drawn to the human α1 anti-trypsin promoter (81 bp).
SEQ ID NO: 4 is drawn to the human α1 anti-trypsin enhancer (54 bp).
The claimed nucleic acid molecule thus encompasses a chimeric molecule comprising a mixture of mouse and human sequences (a minimum of two and maximum of three sequences) of varying lengths that promote expression of a heterogeneous polypeptide in a liver tissue of a mammal.
Regarding function, the claims recite that the claimed nucleic acid molecule will facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
However, the specification provides no description of any sequences other than the full-length sequence set forth in SEQ ID NOs: 1-4 and would provide the function of facilitating transcription of a heterogenous polynucleotide in a liver tissue of a mammal, that would indicate possession at the time of filing for the claimed nucleic acid molecule.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their structure. In the instant case, only the full-length of SEQ ID NOs: 1-4 are sufficiently described to indicate possession of a nucleic acid molecule comprising a mixture of mouse and human promoters and optionally an enhancer and facilitates transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
Further it should be noted that in claims 4 and 16, while (a) and (b) are drawn to a full-length nucleotide sequence the sequence in (c) encompasses a fragment of any length, i.e. “a third polynucleotide having a nucleotide sequence….”. In this regard, the claims encompass a nucleotide sequence for SEQ ID NO: 4 that is only three nucleotides long. Combined with the breadth encompassed by any functional fragment for the claimed nucleotide sequences, the skilled artisan would find that Applicant was not in possession of any nucleotide sequences less than the full-length and still function to facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal. The art teaches that promoter architecture, i.e. the necessary nucleotide sequences required to promote transcription, require precise and specific selection to facilitate transcription in a cell (see Sanchez et al., 2011, PLoS Computation Biology, Vol. 7(3) pgs. 1-20).
In this regard, the specification does not provide any disclosure as to what the complete structure would be of any nucleic acid sequence other than the ones disclosed in the specification that functions as promoters or enhancer as set forth in SEQ ID NOs: 1-4. The specification teaches no structural analysis for said nucleic acid sequences. This is significant since the claims recite a function for promoters and enhancer, facilitating transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
However, the only disclosed nucleic acid sequences that facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal are those disclosed in SEQ ID NOs: 1-4. As of the filing date, there was no known or disclosed correlation between a structure other than the nucleotide sequences set forth in SEQ ID NOs: 1-4 and the facilitation of transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
There is no general knowledge in the art about regarding the activity of the mouse transthyretin promoter, the human α1 anti-trypsin promoter and the human α1 anti-trypsin enhancer to suggest that general similarity of structure confers the activity.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e. other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus.
In the instant case, the only characteristic described, is that the nucleotide sequences function to drive transgene expression in a liver tissue of a mammal (pg. 31 Example 3 of the specification using different combinations of SEQ ID NOs:1-4 set forth in Table 1 and Fig. 5 below).
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The specification does not teach any other identifying characteristics such as domains relating to function/activity or any other related sequences that would guide the artisan to contemplate other nucleic acid sequences that would be encoded by less than the full sequence represented in SEQ ID NOs: 1-4.
While the specification teaches using a nucleic acid molecule comprising different combinations of human and mouse promoters and the option of a human enhancer, the specification teaches using only the full-length sequences set forth SEQ ID NOs: 1-4. However, the claims are not limited to any particular nucleotide sequence within each SEQ ID NO, but rather any combination of nucleotides present in a sequence that would function to facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of functional fragments of the nucleic acid sequences encompassed by the claims at the time of filing. While the structure and function of the full-length sequences for the mouse transthyretin promoter, human α1 anti-trypsin promoter and human α1 anti-trypsin enhancer are known, the specification has not described any other structural characteristics of any nucleic acid sequences that would function to facilitate transcription of a heterogenous polynucleotide in a liver tissue of a mammal with less than the full-length nucleotide sequence.
Applicants' attention is directed to the decision in Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, which clearly states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
With the exception of the sequences referred to above, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieved regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the full-length nucleotide sequences set forth in SEQ ID NOs: 1-4, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In conclusion, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the genus of nucleic acid sequences and fragments thereof as embraced by the claims.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 7-9, 14 and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chuah et al. (WO 2016/146757 A1, cited on IDS filed on 11/22/2022).
Claim Interpretation: the claims recite the limitation “configured to facilitate a transcription of a heterogeneous polynucleotide in a liver tissue of a mammal”, however the specification is silent regarding any configuration of the claimed polynucleotides that would facilitate a transcription of a heterogenous polynucleotide in a liver tissue of a mammal. Thus, it is interpreted that the polynucleotides taught by Chuah, through their 5’-3’ linkage would be “configured” as claimed since the polynucleotides of Chauh facilitate transcription in a liver tissue of a mammal.
Regarding claims 1, 2, 7, 8 and 14, Chuah et al. teach an expression vector (plasmid) comprising multiple regulatory elements to drive liver specific expression (pg. 4 lines 34-37, pg. 6 lines 11-20 and pg. 17 lines 1-22).
Chuah continues to teach that “It has been shown herein that said specific combinations of liver-specific regulatory elements resulted in unexpectedly enhanced liver-specific expression of the transgene, in particular the FIX transgene or FVIII transgene described herein, operably linked thereto” (pg. 19 lines 34-36).
Specifically, Chuah teaches that these regulatory elements can comprise liver-specific promoters arraigned 5’-3’ comprising SEQ ID NO: 6 (mouse transthyretin promoter, reproduced below, which is 100% identical to instant SEQ ID NO: 1) and SEQ ID NO: 64 (human α1 anti-trypsin promoter, reproduced below, which is 100% identical to instant SEQ ID NO: 3) to facilitate transcription of a heterogenous polynucleotide (see pg. 7 lines 15-23, pg. 16 lines 24-35, pg. 22 lines 21-35 and claims 1, 3 and 4).
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Regarding claims 9 and 17, Chuah teaches that a mammalian host cell can comprise the expression vector (pg. 10 lines 8-9 and pg. 30 lines 1-9).
Thus, the teachings of Chuah clearly anticipate the invention of claims 1, 2, 7-9, 14 and 17.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 1, 3, 4, 7, 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chuah et al. (WO 2016/146757 A1, cited on IDS filed on 11/22/2022) in view of Garcia et al. (1995, Eur. J. Immunol., Vol. 25, pgs. 2401-2407).
Claim Interpretation: the claims recite the limitation “configured to facilitate a transcription of a heterogeneous polynucleotide in a liver tissue of a mammal”, however the specification is silent regarding any configuration of the claimed polynucleotides that would facilitate a transcription of a heterogenous polynucleotide in a liver tissue of a mammal. Thus, it is interpreted that the polynucleotides taught by Chuah, through their 5’-3’ linkage would be “configured” as claimed since the polynucleotides of Chauh facilitate transcription in a liver tissue of a mammal.
Regarding claims 1 and 7, Chuah et al. teach an expression vector (plasmid) comprising multiple regulatory elements to drive liver specific expression (pg. 4 lines 34-37, pg. 6 lines 11-20 and pg. 17 lines 1-22).
Chuah continues to teach that “It has been shown herein that said specific combinations of liver-specific regulatory elements resulted in unexpectedly enhanced liver-specific expression of the transgene, in particular the FIX transgene or FVIII transgene described herein, operably linked thereto” (pg. 19 lines 34-36).
Specifically, Chuah teaches that these regulatory elements can comprise liver-specific promoters arraigned 5’-3’ comprising SEQ ID NO: 6 (mouse transthyretin promoter, which is 100% identical to instant SEQ ID NO: 1) and SEQ ID NO: 64 (human α1 anti-trypsin promoter, which is 100% identical to instant SEQ ID NO: 3) to facilitate transcription of a heterogenous polynucleotide (see pg. 7 lines 15-23, pg. 16 lines 24-35, pg. 22 lines 21-35 and claims 1, 3 and 4).
Regarding SEQ ID NO: 4 (human α1 anti-trypsin enhancer) and the use of a third polynucleotide sequence, while Chuah does not teach using the enhancer for human α1 anti-trypsin promoter, Chuah does teach using the enhancer for the mouse transthyretin promoter (pg. 13 line 14) and the benefits of using an enhancer for increasing transgene expression (pg. 47 lines 5-11).
Thus, it would have been obvious to use the human α1 anti-trypsin enhancer (SEQ ID NO: 4) with the human α1 anti-trypsin promoter (SEQ ID NO: 3) in view of the teachings of Garcia et al.
Regarding combining SEQ ID NOs 3 and 4 and claims 3, 4, 15 and 16, Garcia et al. teach combining the sequences for the human α1 anti-trypsin promoter and enhancer to drive expression of tumor necrosis factor receptor type 1 in the liver of mice (see Abstract, Introduction and pg. 2402 section 2.3).
Garcia teaches “The present experiments show that it is possible to obtain transgenic mice which express permanently very high circulating levels of the TNFR1-FcIgG3 transgene product (in the range of 100 μg/ml of blood or above) provided the transgene iy placed under the control of a strong promoter active in the liver. the only organ releasing very large amounts of
proteins into the blood” (pg. 2406 col. 1 parag. 2 lines 1-7).
Regarding SEQ ID NOs: 3 and 4, Garcia teaches nucleotide sequences 100% identical to the human α1 anti-trypsin promoter and enhancer to drive transgene expression.
Instant SEQ ID NO: 3 (human α1 anti-trypsin promoter)
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Thus at the time of filing it would have been prima facie obvious to the ordinary artisan to combine the teachings of Chuah regarding an expression construct comprising the mouse transthyretin promoter and the human α1 anti-trypsin promoter to drive liver-specific transgene expression with the teaching of Garcia regarding the use of the human α1 anti-trypsin enhancer with the human α1 anti-trypsin promoter to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to make such a combination since Chuah teaches that combining an enhancer with its related promoter can increase transgene expression and Garcia teaching that combining the human α1 anti-trypsin promoter and enhancer led to significant transgene expression levels in the liver.
There would have been a reasonable expectation of success that the human α1 anti-trypsin enhancer (SEQ ID NO: 4) could be combined with the expression vector of Chuah since both Chuah and Garcia demonstrate success that combining a promoter with its enhancer will drive transgene expression.
Thus the cite art provides the requisite teachings and motivations to make and use the invention as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID A MONTANARI whose telephone number is (571)272-3108. The examiner can normally be reached M-Tr 8-6.
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/DAVID A MONTANARI/Examiner, Art Unit 1632