The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 2-9, 11-19, 23-31, 33-68, 70, 74-76, 78, 80, 82, 84, 86 are canceled. Claims 1, 10, 20-22, 32, 69, 71-73, 77, 79, 81, 83, 85, 87-91 are pending and under consideration.
Priority: This application is a CON of U.S. Application 18503341, filed November 7, 2023, abandoned, which is a CON of U.S. Application 16839741, filed April 3, 2020, now U.S. Patent 11834479, which is a CON of U.S. Application 16546100, filed August 20, 2019, now U.S. Patent 10696720, which in turn is a CON of U.S. Application 16312901, filed December 21, 2018, abandoned, which is a 371 of PCT/US2017/039133, filed June 23, 2017, which claims benefit of provisional application 62/354650, filed June 24, 2016.
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, 10, 20-22, 32, 69, 71-73, 77, 79, 81, 83, 85, 87-91 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.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to an isolated and modified nucleoside triphosphate transporter from Phaeodactylum tricornutum (PtNTT2) comprising a deletion. Claim 10 is dependent on claim 1 and recites the isolated and modified nucleoside transporter comprises at least 80%, 85%...or 100% sequence identity to SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8. Claim 89 is dependent on claim 1 and recites a kit comprising the isolated and modified nucleoside triphosphate transporter.
Claim 20 is dependent on claim 1 and drawn to a nucleic acid molecule encoding the isolated and modified nucleoside triphosphate transporter from PtNTT2 comprising a deletion.
Claims 71-73, 77, 79, 81, 83, 85, 87 are drawn to an isolated and purified plasmid comprising a nucleic acid molecule encoding modified nucleoside triphosphate transporter from PtNTT2 and a promoter region. Claim 91 is dependent on claim 71 and recites a kit comprising the isolated and purified plasmid.
Claims 22, 32 are drawn to an engineered cell comprising a first nucleic acid molecule encoding a modified nucleoside triphosphate transporter from PtNTT2. Claim 90 is dependent on claim 22 and recites a kit comprising the engineered cell.
Claims 21, 69, 88 are drawn to a method for incorporating one or more unnatural triphosphates or in vivo methods for increasing production of a nucleic acid molecule containing an unnatural nucleotide.
Accordingly, the claims encompass a significantly large genus of recombinant nucleoside triphosphate transporter proteins and a significantly large genus of nucleic acid molecules encoding nucleoside triphosphate transporter proteins from PtNTT2 where the nucleoside triphosphate transporter proteins comprise any number of modifications (or any type of mutations including insertions, deletions, and substitutions with any known amino acid) at any location, in addition to the deletions recited in said claims, that may or may not facilitate crossing of nucleosides through cell membranes and vesicles and a significantly large genus of engineered cells or host organisms comprising said nucleic acid molecules. It is disclosed in the specification that nucleoside transporters (NTs) are a group of membrane transport proteins that facilitate crossing of the nucleosides through cell membranes and vesicles (application publication paragraph 0032). The recited genus of modified nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum are defined through their activity only and do not require any particular structure and comprise any number of modifications (or any type of mutations including insertions, deletions, and substitutions with any known amino acid) at any location, in addition to the deletions recited in said claims, in addition to a terminal and/or internal deletion. As such, the described genera are biomolecules defined solely by their functional characteristics, which is not sufficient characteristic for written description purposes. MPEP 2163. Further, the specification does not provide any discussion of a known correlation between structure and an amino acid sequence having function as a nucleoside triphosphate transporter, sufficient to compensate for the lack of representative number of species provided by the specification or art of record to allow one of ordinary skill to reasonably identify or envision a number of species commensurate with the structural breadth and substantial structural variation encompassed by the recited genera of a nucleoside triphosphate transporter. Accordingly, the claims encompass a significantly large genus of nucleoside triphosphate transporter proteins and/or amino acid sequences having no particular structure that may or may not facilitate crossing of nucleosides through cell membranes and vesicles. The claimed and/or recited cells comprise any cell or microorganism engineered to comprise nucleic acid molecules encoding a nucleoside triphosphate transporter protein from PtNTT2 defined through its activity only and does not require any particular structure and comprises any number of deletions at any location.
The specification discloses three representative species of the respective genus of nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising a deletion. The specification teaches deletion of amino acid residues of 1-65 of full-length PtNTT2 (PtNTT2 66-575), deletion of amino acid residues 23-65 of full-length PtNTT2 (PtNTT2 1-22, 66-575), and deletion of amino acid residues of 1-22 of full-length PtNTT2 (PtNTT2 23-575) (see Table 1). However, the mutations and homologues encompassed by the claims can comprise in addition to the deletion(s), insertions and/or substitutions with any other known amino acid. There is no guidance in the specification regarding which 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% may vary from SEQ ID NO: 4, SEQ ID NO: 6, and SEQ ID NO: 8. It is known that that an unexpected high number of genes encoding putative NTTs have been identified, 6 in Phaeodactylum tricornutum (PtNTT1-6) (Ast et al. p. 3622; IDS). PtNTT1 and PtNTT2 have been characterized. However, PtNTT3-6 have not been characterized (p. 3624) and exhibit low sequence similarities (< 30%) to characterized NTTs (p. 3622). Other than the three representative species of the genus (N-terminally truncated variants of PtNTT2 comprising SEQ ID NO: 4), the specification fails to disclose any other PtNTTs comprising any number of deletions at any location, and in further combination with insertions and/or substitutions with any other known amino acid, and able to facilitate crossing of nucleosides through cell membranes and vesicles. The specification and prior art fail to disclose a correlation between the sequence(s) of PtNTTs and having nucleoside transporting activity. Since there is unpredictability in performance of certain species or subcombinations other than specific variations and/or specific deletions in SEQ ID NO: 4, the skilled artisan is unable to recognize possession of all variants of nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum, comprising any number of deletions, and/or variants having any type of mutation (including insertions, deletions, substitutions with any known amino acid), and further unable to recognize possession of all variants of SEQ ID NOS: 4, 6, and 8 having at least 80% to 99% sequence identity to SEQ ID NOS: 4, 6, and 8, comprising any number of deletions and/or variants having any type of mutation(s) (including insertions, deletions, substitutions with any known amino acid) to SEQ ID NOS: 4, 6, and 8, as encompassed by the claims. Given the lack of additional representative species of enzymatic activities and the variants, including variants of SEQ ID NOS: 4, 6, and 8, as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention. As such, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus. The claimed subject matter is not supported by an adequate written description because a representative number of species has not been described.
The skilled artisan cannot necessarily envision the detailed structures of ALL the modified nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising any type of modification, and variants thereof, including variants of SEQ ID NOS: 4, 6, and 8, and nucleic acid molecules encoding said PtNTTs, where the nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising any modification and variants thereof, are in any plasmid, when expressed in any cell, will facilitate crossing of nucleosides through cell membranes and vesicles, because the specification provides no guidance as to which substitutions and/or deletions and/or additions and which amino acids are essential and critical for the genus of nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum, when expressed or present, and combined with any plasmid, and expressed in any cell, the modified PtNTT will facilitate crossing of nucleosides through cell membranes and vesicles, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the methods of making the claimed invention. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of making it. The compound 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.
The CAFC in UC California v. Eli Lilly, (43 USPQ2d 1398) stated that: "in claims to genetic material, however a generic statement such as 'vertebrate insulin cDNA' or 'mammalian insulin cDNA,' without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define the structure of any and all possible combinations of enzymes that fall within its definition or any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus." It is noted that given that [1] the genus of any cell including any prokaryotes, eukaryotes, extremophiles, etc. expressing or comprising all possible combinations of a broad genus of proteins recited in the claims and/or comprising the genus of any plasmid comprising nucleic acids encoding all possible combinations of a broad genus of proteins recited in claims having essentially any structure while limited only by their functions, wherein the structural diversity within such genus of proteins are widely variant and diverse; and [2] it is highly unpredictable which nucleic acids encoding said proteins would be functionally compatible to facilitate crossing of nucleosides through cell membranes and vesicles, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed genus of inventions.
Claims 1, 10, 20-22, 32, 69, 71-73, 77, 79, 81, 83, 85, 87-91 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 N-terminally truncated variants of PtNTT2 comprising SEQ ID NO: 4 (PtNTT2 66-575; PtNTT2 1-22, 66-575; PtNTT2 23-575), isolated and purified prokaryotic plasmids encoding said N-terminally truncated variants of PtNTT2 comprising SEQ ID NO: 4, E. coli cells comprising said N-terminally truncated of PtNTT2 comprising SEQ ID NO: 4, that facilitate crossing of specific nucleosides through cell membranes and vesicles, and a method of increasing production of specific nucleic acid molecules in E. coli cells comprising expressing N-terminally truncated variants of PtNTT2 comprising SEQ ID NO: 4 (PtNTT2 66-575; PtNTT2 1-22, 66-575; PtNTT2 23-575), does not reasonably provide enablement for all modified nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising any modifications, including deletions, all cells comprising said nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum, that facilitate crossing of nucleosides through cell membranes and vesicles, and methods for increasing production of or incorporating of all nucleic acid molecules in any cell comprising any nucleoside triphosphate transporter protein (from Phaeodactylum tricornutum) comprising a deletion or any modifications. 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 claims are directed to recombinant nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising a deletion, nucleic acid molecules encoding said nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising a deletion or modifications, cells comprising said nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising a deletion or modifications, and methods of incorporating or transporting unnatural nucleoside triphosphates. The claims are broader than the enablement provided by the disclosure.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
(A) The breadth of the claims: Claim 1 is drawn to an isolated and modified nucleoside triphosphate transporter from Phaeodactylum tricornutum (PtNTT2) comprising a deletion. Claim 10 is dependent on claim 1 and recites the isolated and modified nucleoside transporter comprises at least 80%, 85%...or 100% sequence identity to SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8. Claim 89 is dependent on claim 1 and recites a kit comprising the isolated and modified nucleoside triphosphate transporter.
Claim 20 is dependent on claim 1 and drawn to a nucleic acid molecule encoding the isolated and modified nucleoside triphosphate transporter from PtNTT2 comprising a deletion.
Claims 71-73, 77, 79, 81, 83, 85, 87 are drawn to an isolated and purified plasmid comprising a nucleic acid molecule encoding modified nucleoside triphosphate transporter from PtNTT2 and a promoter region. Claim 91 is dependent on claim 71 and recites a kit comprising the isolated and purified plasmid.
Claims 22, 32 are drawn to an engineered cell comprising a first nucleic acid molecule encoding a modified nucleoside triphosphate transporter from PtNTT2. Claim 90 is dependent on claim 22 and recites a kit comprising the engineered cell.
Claims 21, 69, 88 are drawn to a method for incorporating one or more unnatural triphosphates or in vivo methods for increasing production of a nucleic acid molecule containing an unnatural nucleotide.
Accordingly, the claims encompass a significantly large genus of recombinant nucleoside triphosphate transporter proteins and a significantly large genus of nucleic acid molecules encoding nucleoside triphosphate transporter proteins from PtNTT2 where the nucleoside triphosphate transporter proteins comprise any number of modifications (or any type of mutations including insertions, deletions, and substitutions with any known amino acid) at any location, in addition to the deletions recited in said claims, that may or may not facilitate crossing of nucleosides through cell membranes and vesicles and a significantly large genus of engineered cells or host organisms comprising said nucleic acid molecules. It is disclosed in the specification that nucleoside transporters (NTs) are a group of membrane transport proteins that facilitate crossing of the nucleosides through cell membranes and vesicles (application publication paragraph 0032). The recited genus of modified nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum are defined through their activity only and do not require any particular structure and comprise any number of modifications (or any type of mutations including insertions, deletions, and substitutions with any known amino acid) at any location, in addition to the deletions recited in said claims, in addition to a terminal and/or internal deletion. As such, the described genera are biomolecules defined solely by their functional characteristics. Further, the specification does not provide any discussion of a known correlation between structure and an amino acid sequence having function as a nucleoside triphosphate transporter, sufficient to compensate for the lack of representative number of species provided by the specification or art of record to allow one of ordinary skill to reasonably identify or envision a number of species commensurate with the structural breadth and substantial structural variation encompassed by the recited genera of a nucleoside triphosphate transporter. Accordingly, the claims encompass a significantly large genus of nucleoside triphosphate transporter proteins and/or amino acid sequences having no particular structure that may or may not facilitate crossing of nucleosides through cell membranes and vesicles. The claimed and/or recited cells comprise any cell or microorganism engineered to comprise nucleic acid molecules encoding a nucleoside triphosphate transporter protein from PtNTT2 defined through its activity only and does not require any particular structure and comprises any number of deletions at any location.
The mutations and homologues encompassed by the claims can comprise in addition to the deletion(s), insertions and/or substitutions with any other known amino acid. There is no guidance in the specification regarding which 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% may vary from SEQ ID NO: 4, SEQ ID NO: 6, and SEQ ID NO: 8. The specification and prior art fail to disclose a correlation between the sequence(s) of PtNTTs and having nucleoside transporting activity. Since there is unpredictability in performance of certain species or subcombinations other than specific variations and/or specific deletions in SEQ ID NO: 4, the skilled artisan is unable to recognize possession of all variants of SEQ ID NOS: 4, 6, and 8 having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NOS: 4, 6, and 8, comprising any number of deletions, and/or variants having any type of mutation (including insertions, deletions, substitutions with any known amino acid) to SEQ ID NOS: 4, 6, and 8, as encompassed by the claims.
The nature and breadth of the claimed invention encompasses any nucleoside triphosphate transporter protein from Phaeodactylum tricornutum, comprising any number of deletions, and/or variants having any type of mutation (including insertions, deletions, substitutions with any known amino acid), nucleic acid molecules encoding said PtNTTs, and any cell comprising said PtNTTs. Thus, there could be a myriad of variant PtNTTs having sufficient activity, wherein the variant PtNTTs may or may not retain facilitate crossing of any nucleosides through cell membranes and vesicles when expressed in the engineered cell and combined with other biological pathway enzymes and proteins already present in the cell. Therefore, for the instant claimed invention, it would require an undue burden of experimentation for a skilled artisan to determine exactly which derivatives and/or variants retain biological activity and with which cell will facilitate crossing of which nucleosides through cell membranes and vesicles and would be functionally compatible with biological pathway enzymes and proteins already present in any host cell/organism/microorganism that is to be engineered.
(B) The nature of the invention: The nature of the invention is engineering novel nucleoside triphosphate transporter proteins to facilitate crossing of nucleosides through cell membranes and vesicles.
(C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: According to MPEP 2164.03, “…what is known in the art provides evidence as to the question of predictability.” Regarding the scope of proteins and/or the nucleic acid molecules encoding the proteins, it is noted that the amino acid sequence of a polypeptide determines said polypeptide’s structural and functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. See, e.g., MPEP 2144.08.II.A.4.(c), which states, “[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution (“the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein.” Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990).”
In this instance, it is known that that an unexpected high number of genes encoding putative NTTs have been identified, 6 in Phaeodactylum tricornutum (PtNTT1-6) (Ast et al. p. 3622). PtNTT1 and PtNTT2 have been characterized. However, PtNTT3-6 have not been characterized (p. 3624) and exhibit low sequence similarities (< 30%) to characterized NTTs (p. 3622).
The nature of the invention is such that many different polypeptides that are substantially similar to PtNTT and/or nucleic acid molecules encoding many different polypeptides that are substantially similar to PtNTT may or may not retain biological activity to facilitate crossing of nucleosides through cell membranes and vesicles, when expressed. The state of the prior art is that even proteins that are highly similar to the wild-type protein are at times not fully active. The relative level of skill in this art is very high. Further, given that the genus of any plasmid and/or the genus of any cell including any prokaryotes, eukaryotes, extremophiles, etc. comprising nucleic acids encoding all possible combinations of a broad genus of proteins recited in claims having essentially any structure while limited only by their functions, wherein the structural diversity within such genus of proteins or enzymes are widely variant and diverse; and that it is highly unpredictable which nucleic acids encoding said proteins or which protein(s) or possible combinations with other proteins/enzymes when introduced into a heterologous organism/microorganism would be functionally compatible with other proteins/enzymes already present in the host organism/microorganism to facilitate crossing of nucleosides through cell membranes and vesicles, it would require an undue burden of experimentation for a skilled artisan to determine exactly which derivatives and/or variants retain biological activity and facilitate crossing of which nucleosides through cell membranes and vesicles and would be functionally compatible with biological pathway enzymes and proteins already present in which host organism/microorganism and when expressed by which plasmid. The predictability as to which plasmid encoding or expressing which PtNTT proteins and variants in which engineered cell will have which type of activity or productivity is zero.
“[I]f one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains, then there is lack of predictability in the art.” See MPEP § 2164.03.
(F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The specification discloses three representative species of the respective genus of nucleoside triphosphate transporter proteins from Phaeodactylum tricornutum comprising a deletion. The specification teaches deletion of amino acid residues of 1-65 of full-length PtNTT2 (PtNTT2 66-575), deletion of amino acid residues 23-65 of full-length PtNTT2 (PtNTT2 1-22, 66-575), and deletion of amino acid residues of 1-22 of full-length PtNTT2 (PtNTT2 23-575) (see Table 1). However, the mutations and homologues encompassed by the claims can comprise in addition to the deletion(s), insertions and/or substitutions with any other known amino acid. There is no guidance in the specification regarding which 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1% may vary from SEQ ID NO: 4, SEQ ID NO: 6, and SEQ ID NO: 8. Further, the specification discloses only specific plasmids comprising nucleic acids encoding the representative species of PtNTT2 and a single representative species of the genus of cells comprising a nucleoside triphosphate transporter from Phaeodactylum tricornutum, i.e. an E. coli cell comprising a N-terminally truncated variant of PtNNT2 (PtNNT2 66-575). The specification does not disclose any other plasmids, besides plasmids for E. coli cells, engineered to comprise a PtNTT and does not disclose a correlation between the sequence(s) of PtNTTs and having nucleoside transporting activity. It was further even disclosed that expression of PtNTT2(66-575) in E. coli had different effects. PtNTT2(66-575) in E. coli C41(DE3) resulted in lower toxicity relative to the full length PtNTT2, but reduced uptake of [alpha-32P]-dATP, possibly due to reduce expression; expression of PtNTT2 in E. coli BL21(DE3) resulted in increased levels of [alpha-32P]-dATP uptake with little increased toxicity, but the strain was toxic due to higher level of T7 RNAP (application publication paragraph 0204-0205). The specification does not disclose any other cells engineered to comprise a PtNTT and does not disclose a correlation between the sequence(s) of PtNTTs and having nucleoside transporting activity. Since there is unpredictability in performance of certain species or subcombinations other than specific variations, the skilled artisan is unable to recognize possession of all nucleic acid molecules encoding a modified nucleoside triphosphate transporter protein from Phaeodactylum tricornutum comprising any number of deletions, and/or variants having any type of mutation (including insertions, deletions, substitutions with any known amino acid), and all cells comprising said nucleic acid molecules and proteins, as encompassed by the claims. Thus, searching for and/or designing nucleic acid molecules encoding PtNTTs that are able to facilitate crossing of nucleosides through cell membranes and vesicles from all nucleic acid molecules encoding PtNTT1-6, where further at least PtNTT3-6 have yet to be characterized and exhibit sequence similarity of less than 30% with other NTTs, and further searching for and/or selecting an appropriate plasmid and promoter(s) to express the PtNTTs and an appropriate host organism/microorganism to express the PtNTTs, such that they facilitate crossing of all nucleosides through cell membranes and vesicles is well outside the realm of routine experimentation and predictability in the art of success is extremely low. The amount of experimentation to identify such nucleic acids encoding said proteins and variants thereof, is enormous. While methods of mutagenesis are known, it is not routine in the art to screen for all modifications to an unexpected high number of genes encoding PtNTTs for the desired activity and all cells comprising said PtNTTs, able to facilitate crossing of nucleosides through all cell membranes and vesicles.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, and the high degree of unpredictability as evidenced by the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
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 21, 69, 88 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 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps and/or elements, such omission amounting to a gap between the steps and/or elements. See MPEP § 2172.01. The omitted steps are: the steps that are required and/or needed to carry out the method of incorporating one or more unnatural triphosphates during the synthesis of a nucleic acid molecule.
Claim 69 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps and/or elements, such omission amounting to a gap between the steps and/or elements. See MPEP § 2172.01. The omitted steps are: the steps that are required and/or needed to carry out the method of increasing production of a nucleic acid molecule containing an unnatural nucleotide.
Claim 88 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps and/or elements, such omission amounting to a gap between the steps and/or elements. See MPEP § 2172.01. The omitted steps are: the steps that are required and/or needed to carry out the method of increasing production of a nucleic acid molecule containing an unnatural nucleotide.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 89-91 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 89-91 are product claims dependent on claims 1, 22, and 71, respectively. The claims do not recite any additional components to the product that further limit the claims. The recitation of an intended use (i.e. kit) in a product claim does not further limit the claims. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by UPI0001D42ADE (Database Uniparc Accession No. available May 30, 2010; IDS). UPI0001D42ADE teaches a 479 residue amino acid sequence where residues 1-479 aligns with residues 33-511 of SEQ ID NO: 4 (disclosed in the instant specification as an N-terminally truncated variant of PtNTT2); therefore, the amino acid sequence of UPI0001D42ADE can be deemed to anticipate instant claims 1, 10.
Claims 1, 20, 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ast et al. (2009 PNAS 106(9): 3621-3626; IDS). Ast et al. teach PtNTT1 and PtNTT2 presequences or prepeptides (residues 1-91 of PtNTT1 and residues 1-65 of PtNTT2) fused to GFP (p. 3623-3624, also Fig. S4A); therefore, Ast et al. can be deemed to teach a PtNTT comprising a deletion (instant claim 1).
Regarding instant claims 20, 22, Ast et al. teach the PtNTT1 and PtNTT2 presequences or prepeptides fused to GFP are expressed in P. tricornutum (p. 3623-3625); therefore, Ast et al. can be deemed to teach isolated P. tricornutum cells comprising a PtNTT comprising a deletion and a nucleic acid molecule encoding a PtNTT comprising a deletion.
Claim Rejections - 35 USC § 103
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.
Claims 71, 73, 77, 85, 87, 91 are rejected under 35 U.S.C. 103 as being unpatentable over Ast et al. (2009 PNAS 106(9): 3621-3626; IDS) in view of Cantrell (2003 Methods in Molecular Biology vol. 235: E. coli Plasmid Vectors: 257-275; IDS). Ast et al. disclose PtNTT1 and PtNTT2 presequences or prepeptides (residues 1-91 of PtNTT1 and residues 1-65 of PtNTT2) fused to GFP (p. 3623-3624, also Fig. S4A); therefore, Ast et al. can be deemed to disclose a PtNTT with an amino acid sequence comprising a deletion. Ast et al. disclose generation of constructs for expression in E. coli (p. 3625). Ast et al. do not specifically teach a promoter region selected from a pSC plasmid or lacZYA locus.
Cantrell discloses vectors for the expression of recombinant proteins in E. coli (p. 257). It is disclosed that E. coli is the most commonly used and best characterized organism for overexpressing foreign and nonforeign proteins (p. 257). Cantrell discloses that the pSC plasmid or vector is a known E. coli vector and enables many proteins that are toxic to cells when in other vectors, the pET system, to be tolerated (p. 261). It is further disclosed that promoters commonly used in E. coli expression vectors include among others, the lac system based on the promoter of the E. coli lac operon, lac, lacUV5, tac (p. 261-262).
It would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to combine the references and arrive at the claimed isolated and purified plasmid comprising a nucleic acid molecule encoding a modified nucleoside triphosphate transporter from Phaeodactylum tricornutum (PtNTT2); and a promoter region selected from a pSC plasmid or lacZYA locus; and a cell comprising said plasmid (instant claims 71, 73, 77, 85, 87, 91). The motivation to do so is given by the prior art. Ast et al. disclose expressing PtNTT amino acid sequences comprising a deletion. Ast et al. disclose generating constructs for expression in E. coli cells. Cantrell discloses E. coli expression vectors and promoters commonly used in said expression vectors, including the claimed promoter regions. Therefore, one of ordinary skill would have reasonable motivation to substitute an E. coli expression vector comprising a lac promoter as disclosed in Cantrell for the plasmid encoding PtNTT amino acid sequences comprising a deletion in Ast et al. because there was interest in nucleoside transport systems. One of ordinary skill would have a reasonable expectation of success because promoters commonly used in E. coli expression vectors were known and used for expressing foreign proteins.
Regarding instant claim 91, in In re Haller, 73 USPQ 403 (CCPA 1947), the Court held that an old compound, packaged and labeled to show its use, is not patentable. The packaging of a known compound and the application of an appropriate label thereto does not involve invention over the known compound. In this instance, the isolated and purified plasmid comprising a nucleic acid molecule encoding a modified nucleoside triphosphate transporter from PtNTT2 of Ast et al. in view of Cantrell noted above can reasonably be used in a kit for commercial purposes.
Claims 89-90 are rejected under 35 U.S.C. 103 as being unpatentable over Ast et al. (2009 PNAS 106(9): 3621-3626; IDS). The teachings of Ast et al. over at least instant claims 1, 22 are noted above.
Regarding instant claims 89-90, in In re Haller, 73 USPQ 403 (CCPA 1947), the Court held that an old compound, packaged and labeled to show its use, is not patentable. The packaging of a known compound and the application of an appropriate label thereto does not involve invention over the known compound. In this instance, the PtNTT comprising a deletion and cell comprising the noted PtNTT of Ast et al. above can reasonably be used in a kit for commercial purposes.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21, 69, 88 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11834479 (‘479). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘479 patent claims are drawn to methods of incorporating one or more unnatural nucleoside triphosphates into a nucleic acid molecule and methods of increasing production of a nucleic acid molecule containing an unnatural nucleotide comprising a modified nucleoside triphosphate transporter and/or cell comprising a modified nucleoside triphosphate transporter.
Claims 21, 69, 88 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10696720 (‘720). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘720 patent claims are drawn to methods of incorporating one or more unnatural nucleoside triphosphates into a nucleic acid molecule and methods of increasing production of a nucleic acid molecule containing an unnatural nucleotide comprising a modified nucleoside triphosphate transporter and/or cell comprising a modified nucleoside triphosphate transporter.
Claims 1, 10, 20, 22, 32, 71-73, 77, 79, 81, 83, 85, 87, 89-91 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10696719 (‘719) in view of Cantrell (2003 Methods in Molecular Biology vol. 235: E. coli Plasmid Vectors: 257-275; IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the ‘719 patent claims are drawn to a modified PtNTT comprising a deletion, a nucleic acid molecule encoding the modified PtNTT comprising a deletion, and a cell comprising the modified PtNTT comprising a deletion. The deficiency of the ‘719 patent claims to not explicitly disclose a plasmid comprising the nucleic acid molecule(s) encoding the modified PtNTT comprising a deletion is remedied by Cantrell for the reasons noted above, which disclose vectors for the expression of recombinant proteins in E. coli (Cantrell p. 257). Therefore, it would have been obvious to incorporate an E. coli expression vector comprising a lac promoter as disclosed in Cantrell to comprise the nucleic acid molecules encoding the PtNTT amino acid sequences of the ‘719 patent claims because plasmids and promoters commonly used in E. coli expression vectors were known and used for expressing foreign proteins.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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