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 .
1. Claims 1-14 have been amended.
Claims 1-14 are pending and under examination.
2. The objections to claims 2-10, 12, and 13 are withdrawn in response to the amendments filed on 12/02/2025.
Claim Objections
3. Claim 1 is objected to because of the recitation “a heparin-like substance” in step (3). Correction to “the heparin-like substance” is required.
4. Claim 11 is objected to because of the recitation ” the extracellular domain of”.
Correction to “the extracellular domain of SDC” is required.
5. Claim 14 is objected to because of the recitation ”a mammalian cell” in line 2. Correction to ”the mammalian cell” is required.
Claim Rejections - 35 USC § 112(a) – written description
6. 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.
7. Claims 4-6 and 8-10 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.
Adequate written description requires more than a mere statement that it is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC1993). The Guidelines for the Examination of Patent Application Under the 35 U.S.C.112, 1"Written Description Requirement" makes it clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species disclosures of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, see especially page 1106 3rd column).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail such that the Artisan can reasonably conclude the inventors had possession of the claimed invention. Such possession may be demonstrated by describing the claimed invention with all its limitations using such descriptive means as words, structures, figures, diagrams, and/or formulae that fully set forth the claimed invention. Possession may be shown by an actual reduction to practice, showing that the invention was "ready for patenting", or by describing distinguishing identifying characteristics sufficient to show that the Applicants were in possession of the claimed invention (January 5, 2001, Fed. Reg., Vol. 66, No. 4, pp.1099-11).
Claims 4-6 are broadly drawn to a genus of proteins comprising deletions, substitutions, or additions to SEQ ID NOs: 1-3 (the amino acid sequences of SDC, NDST2, and Hs3st1, respectively) while maintaining the wild type activity. Claims 8-10 are broadly drawn to a genus of nucleic acids comprising deletions, substitutions, or additions to SEQ ID NOs: 4-6 (the nucleic acids encoding SDC, NDST2, and Hs3st1, respectively) while encoding proteins exhibiting wild type activity. Thus claims 4-6 encompass a wide and variable genus of fragments derived from SEQ ID NO: 1-3 and also proteins comprising substitutions, deletions, insertions, additions, and/or inversion of one or several amino acids in SEQ ID NOs: 1-3, which may or may not be active. Claims 8-10 encompass a wide and variable genus of fragments derived from SEQ ID NO: 4-6 and also nucleic acids comprising substitutions, deletions, insertions, additions, and/or inversion of one or several nucleotides in SEQ ID NOs: 4-6, which may or may not encode an enzymatically active protein or a functional SDC. Therefore, claims 4-6 and 8-10 encompass a wide and variable genus of proteins and nucleic acids the structure of which is not sufficiently disclosed in the specification and the claims.
In analyzing whether the written description requirement is met for the genus claims, it is determined whether representative numbers of species have been described by their complete structure and functional characteristics. When the claims are analyzed in light of the specification, the variant protein can be any variant or fragment as long as it has enzymatic/SDC activity; the encoding nucleic acid can be any variant or fragment as long as it encodes the protein variant or fragment. The genus of variants and fragments is very large; and a great deal of variability is encompassed by the instant claims. With the exception of the amino acid sequences set forth by SEQ ID NOs: 1-3 (SDC, NDST2, and Hs3st1, respectively) and the encoding SEQ ID NOs: 4-6 , the specification fails to describe additional representative species of the amino acid/nucleotide variant sequences or fragments mentioned above. The genera of variants and fragments are described by their function, but the specification does not provide any disclosure as to what would have been the complete structure of sufficient number of species of the claimed genera. Additionally, the specification does not describe what would have been the identifying characteristics, such as specific features and functional attributes, of the different variants and fragments. Applicant has not provided any information besides the characterization of the genus as having an enzymatic/SDC activity. This limited characterization, however, does not indicate that the applicant had possession of the claimed genera of variants and fragments. The specification fails to disclose what requirements a variant or fragment must meet to have SDC, NDST2, and Hs3st1, a feature deemed essential for the instant invention. Applicant is relying upon biological activity and the disclosure of one amino acid/encoding nucleic acid pair for each SDC, NDST2, and Hs3st1 to support the entire genera. It is well known that minor structural differences among even structurally related compounds can result in substantially different biology. For example, Seffernick et al. (J. Bacteriol., 2001, 183: 2405-2410) teach that proteins that are 98% identical could have distinct activities (see Abstract). Witkowski et al. (Biochemistry, 1999, 38: 11643-11650) teach that a change of a single amino acid can result in a different function (see Abstract). One of skill in the art would know that a change of even one amino acid residue in the claimed sequence could render an inactive protein or a protein with a different activity. One of skill in the art would not know where modifications could be introduced such as to preserve activity. Therefore, one of skill in the art would not recognize the applicant to be in possession of the entire claimed genera.
With respect to the limitation of at least 90% homology, the claims encompass in their breadth any amino acid or nucleic acid fragment or complement having 90% identity to the amino acid/nucleic acid sequences. The fragments can be any sequence in SEQ ID NO: 1-6 or other unrelated nucleic acid molecule with the claimed percent identity, for example the fragment can have the claimed percent identity over a contiguous or non-contiguous portions of the claimed sequences and could be derived from the claimed sequences or from sequences that are distinct from the claimed sequences. Minor structural differences among even structurally related compounds can result in substantially different biology (see the teachings of Seffernick et al. above). Therefore, structurally unrelated sequences having at least 90% identity with SEQ ID NO: 1-6 would be expected to have greater differences in their activities.
The same considerations apply to the hybridization language in claims 8-10. The fact that two nucleic acid sequences hybridize under stringent conditions does not in and of itself require that the two sequences be derived from the same nucleic acid. Furthermore, it is well known in the art that hybridization could occur between sequences based upon short stretches of 100% identity. Thus, an enormous variability with respect to the full-length nucleic acid is possible. There is insufficient written description about the structure associated with the function of a nucleic acid sequence which hybridizes under stringent conditions to SEQ ID NO 4-6. Since the specification fails to describe additional representative species of nucleic acid mentioned above, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus.
In conclusion, the limited information provided by the specification is not sufficient to reasonably convey to one of skill in the art that applicant invented what is claimed.
Claim Rejections - 35 USC § 103
8. 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.
9. Claims 1-5, 7-9, and 11-14 are rejected under 35 U.S.C. 103 as being unpatentable over Baik et al. (Metabolic Engineering, 2012, 14: 81-90), as evidenced by Bernfield et al. (Phil. Trans. R. Soc. Lond. B, 1990, 327: 171-186).
Baik et al. teach (1) a recombinant CHO cell obtained by transfecting the CHO cell with plasmids encoding the mouse Hs3st1 and the human NDST2; and (2) using the recombinant CHO cell to produce bioengineered heparin (claims 1-3, 12, and 13) (see Abstract; p. 83, column 1, second full paragraph; p. 84, column 1; p. 85, column 2, first paragraph; p. 89, column 1).
Baik et al. do not teach that the recombinant CHO cell comprises a gene encoding the extracellular domain of syndecan (claims 1, 11, and 14). However, Baik et al. teach that overexpressing the syndecan core protein would greatly simplify heparin purification as it will facilitate increased secretion, and thus, it will eliminate the need for cell lysis to recover the heparin (see p. 87, column 2). Based on these teachings, one of skill in the art would have found obvious to modify the recombinant CHO cell by transfecting it with an expression vector encoding the core protein of syndecan to achieve the predictable result of simplifying the purification process. As evidenced by Bernfield et al. the core protein is the ectodomain (extracellular domain) of syndecan (see p. 175, Fig. 1).
Since the specification discloses that SEQ ID NOs: 4 and 5 used to obtain the claimed recombinant cell are the NDST2- and Hs3st1-encoding nucleic acids of Baik et al. (see [0078]), Baik et al. teach SEQ ID NOs: 2-5 (claims 4, 5, 8 and 9).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
10. Claims 1-14 are rejected under 35 U.S.C. 103 as being unpatentable over Baik et al. as evidenced by Bernfield et al., in further view of Daisuke et al. (WO 15/076282). The English language translation of the WO 15/076282 document is U.S. Patent No. 10,370,450; the passages indicating the teachings of the WO 15/076282 document are based on its English language translation, i.e., the U.S. Patent No. 10,370,450.
The teachings of Baik et al. are applied as above for claims 1-5, 7-9, and 11-14. Baik et al. do not specifically teach that the extracellular domain of syndecan is set forth by SEQ ID NO: 1, which is encoded by SEQ ID NO: 6 (claims 6 and 10). However, it is noted that there is no evidence of record indicating that specifically using SEQ ID NO: 1 leads to unexpected results. One of skill in the art would have found obvious to use any syndecan to achieve the predictable result of achieving increased secretion of bioengineered heparin. Furthermore, Daisuke et al. teach the extracellular domain of syndecan-1 set forth by SEQ ID NO: 10 and encoded by SEQ ID NO: 9 (see column 2, lines 34-52). These sequences have a length of 250 amino acids and 750 nucleotides, respectively. As evidenced by the attached Sequence Alignments, the amino acids 1-229 of SEQ ID NO: 10 and 1-687 of SEQ ID NO: 9 are identical to the claimed SEQ ID NO: 1 and SEQ ID NO: 6, respectively. Using these sequences to obtain the recombinant CHO cell expressing the extracellular domain of syndecan would have been obvious to one of skill in the art to achieve the predictable result of simplifying the purification process.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
11. Written description
The arguments have been considered but not found persuasive because they are mere statements not supported by the specification. The disclosure of wild type sequences is not enough to support the broad genera recited in the claims.
While the claims were amended to recite at least 90% homology, it is noted that homology of at least 90% does not necessarily mean that biological function is preserved. It is noted that the claims do not require at least 90% homology over the entire length of the claimed sequences. Thus, the claims encompass any fragment derived from the claimed sequences or unrelated nucleic acids having the claimed percent homology over a contiguous or non-contiguous portions of the claimed sequences. The specification does not disclose such fragments.
In case of homology over the entire length, the art teaches that a change of even one amino acid residue could render an inactive protein or a protein with a different activity. For example, Seffernick teaches that proteins which are 98% identical could have distinct activities; Witkowski teaches that a change of a single amino acid can result in a different function.
The applicant points to [0009]-[0010], [0040], [0048], and [0056] in the specification. However, [0009] discloses related art; [0010] discloses that the invention provides a purification method; [0040] discloses vectors which to be used in the claimed method; [0048] and [0056] disclose method steps. None of these paragraphs provides sufficient number of species of the claimed genera; none of these paragraphs provides the necessary structure-function relationship, and thus, none of these paragraphs indicates where and what modifications could be introduced into the claimed sequences such as to preserve activity.
35 U.S.C. 103
The applicant argues that that Baik’s disclosure merely provides a concept and does not describe how to achieve the desired effect. The applicant argues that, based on Baik, one of skill in the art would not have been able to reasonably predict which protein could be used to simplify heparin purification without actual experimentation.
This is not found persuasive. While the specification discloses many candidate proteins, an obviousness-type rejection is based on the teachings in the prior art, not on the specification. Baik does not disclose many candidate proteins. Baik specifically points to syndecan core as facilitating secretion. Based on Baik’s disclosure, one of skill in the art would have reasonably concluded and would have reasonably expected that syndecan core would work. Additionally, unless undue, further experimentation is not evidence for non-obviousness. Transfecting the recombinant CHO cells with expression vector encoding the syndecan core would have only entailed routine experimentation. As evidenced by Baik, monitoring secretion would have also entailed routine experimentation.
The argument that the remaining differenced do not remedy the deficiencies in Baik is not found persuasive because there is no deficiency to be remedied in Baik’s teachings.
Conclusion
12. THIS ACTION IS MADE FINAL. 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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/ILEANA POPA/Primary Examiner, Art Unit 1633