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 .
Claims 1-12 are pending and under consideration in this Office Action.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-12 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a broad and widely varying genus of recombinant hyaluronidase PH2O or a genus of variants thereof comprising a substitution of one or more amino acid residues and optionally comprising a deletion of one or more of N-terminal and/or C-terminal amino acid residues in an amino acid sequence of the hyaluronidase PH2O, wherein the hyaluronidase PH2O or variant thereof comprises one or more N-glycan,wherein a sialylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 25%, wherein the sialylation content is a sum of percentage content of N-glycan containing sialic acid,wherein a galactosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 68%, wherein the galactosylation content is a sum of percentage content of N- glycans containing galactose,wherein a mannosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 40 to 63%, wherein the mannosylation content is aa sum of percentage content of N- glycans containing mannose, wherein a sum of the galactosylation content and the mannosylation content is no more than 100%, and wherein an enzymatic activity of the hyaluronidase PH20 or variant thereof is 10,000 units/mL or more, where the genus of variants of any amino acid sequence and structure includes PH20 variants comprising substitutions of one or more amino acid residues.
According to MPEP 2163:
“For each claim drawn to a genus: 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 (see i)(A), above), reduction to drawings (see i)(B), above), 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 i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014)…”
According to MPEP 2163.02:
“The courts have described the essential question to be addressed in a description requirement issue in a variety of ways. An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed. The test for sufficiency of support in a parent application is whether the disclosure of the application relied upon "reasonably conveys to the artisan that the inventor had possession at that time of the later claimed subject matter." Ralston Purina Co. v. Far-Mar-Co., Inc., 772 F.2d 1570, 1575, 227 USPQ 177, 179 (Fed. Cir. 1985) (quoting In re Kaslow, 707 F.2d 1366, 1375, 217 USPQ 1089, 1096 (Fed. Cir. 1983)).”
The reference of Chica et al. (Curr Opin Biotechnol. 2005 Aug;16(4):378-84; PTO 892) teaches that the complexity of the structure/function relationship in enzymes has proven to be the factor limiting the general application of rational enzyme modification and design, where rational enzyme modification and design requires in-depth understanding of structure/function relationships. The reference of Singh et al. (Curr Protein Pept Sci. 2017, 18, 1-11; PTO 892) reviews protein engineering methods including directed evolution, rational design, semi-rational design, and de-novo design; and states that despite the availability of a growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see entire publication especially Figs.1 and 3, and page 7, left column, lines 8-17). The reference teachings only provide guidance for searching and screening for the genus of genus of recombinant hyaluronidases PH20 or a genus of variants thereof.
The specification as originally filed does not disclose a representative number of species encompassed by the claimed genus by actual reduction to practice including any host cells thereof other than CHO host cells. The specification as originally filed does not provide a correlation between function and structure to enable one of ordinary skill in the art to predict which amino acid sequences, structures, and specific substitution mutations correlate with increased hyaluronidase activity.
The specification discloses a method for producing recombinant hyaluronidase PH20 comprising the amino acid sequence of SEQ ID NO: 1 comprising culturing CHO host cells expressing said recombinant hyaluronidase PH20 comprising the amino acid sequence of SEQ ID NO: 1 at a culture temperature of 35°C to 38°C until an integral viable cell density of the host cells reaches 20x106 to 120x106 cells x day/mL; and (2) decreasing the culture temperature to 28°C to 34°C and then culturing the host cells for 2 to 18 days; while maintaining the culture temperature: (a) wherein the residual glucose concentration in the medium is maintained at 0.001 g/L to 4.5 g/L during the culture period; and/or (b) wherein the pH of the culture medium is maintained at 6.8 ~ 7.2; wherein a sialylation content of an N-glycan of the produced recombinant hyaluronidase PH20 is 1 to 38%, and wherein a hyaluronidase activity in the culture medium is 10,000 units/mL or more.
Hence, the specification does not provide sufficient written description to inform one of ordinary skill in the art that applicants were in possession at the time the application was filed of the claimed genus of recombinant hyaluronidase PH2O or a genus of variants thereof comprising a substitution of one or more amino acid residues and optionally comprising a deletion of one or more of N-terminal and/or C-terminal amino acid residues in an amino acid sequence of the hyaluronidase PH2O, wherein the hyaluronidase PH2O or variant thereof comprises one or more N-glycan,wherein a sialylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 25%, wherein the sialylation content is a sum of percentage content of N-glycan containing sialic acid,wherein a galactosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 68%, wherein the galactosylation content is a sum of percentage content of N- glycans containing galactose,wherein a mannosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 40 to 63%, wherein the mannosylation content is aa sum of percentage content of N- glycans containing mannose,wherein a sum of the galactosylation content and the mannosylation content is no more than 100%, and wherein an enzymatic activity of the hyaluronidase PH20 or variant thereof is 10,000 units/mL or more, where the genus of variants of any amino acid sequence and structure includes PH20 variants comprising substitutions of one or more amino acid residues.
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 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 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by EP3037529 (06/29/2016; IDS filed 11/07/2024).
EP3037529 teaches host cells expressing human-derived pH20 hyaluronidase are cultured in a medium at 37°C and pH 7.2 for 14 days; an integral cell density increases with the culture period; 25% of sialic acid is contained; and an enzymatic activity is 1600 units/mL (see entire publication and abstract especially paragraphs [0322], [0327], [0328] and [0358] and Tables 10, 11, 12 and 28). Thus, the reference teachings anticipate the claimed invention.
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 of this title, 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 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over EP3037529 (06/29/2016; IDS filed 11/07/2024) in view of Chen et al. (Constitutive expression of recombinant human hyaluronidase PH20 by Pichia pastoris. Journal of Bioscience and Bioengineering. 2016, vol. 122, no. 6, pages 673-378; IDS filed 11/07/2024), Frost et al. (Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin. Drug Deliv. 2007, vol. 4, no. 4, pages 427-440; IDS filed 11/07/2024), Bornscheuer et al. (Curr Protoc Protein Sci. 2011 Nov;Chapter 26:Unit26.7; PTO 892)
EP3037529 teaches host cells expressing human-derived pH20 hyaluronidase are cultured in a medium at 37°C and pH 7.2 for 14 days; an integral cell density increases with the culture period; 25% of sialic acid is contained; and an enzymatic activity is 1600 units/mL (see entire publication and abstract especially paragraphs [0322], [0327], [0328] and [0358] and Tables 10, 11, 12 and 28).
The teachings of the reference differ from the claims in that the reference does not teach the claimed recombinant hyaluronidase PH2O or a variant thereof.
Bornscheuer et al. teach protein engineering strategies to improve or change the properties of proteins, teach concepts for protein engineering using rational design including substitution and/or deletion of amino acids, directed evolution, and combinations of them where different strategies are presented for identifying the best mutagenesis method, how to identify desired variants by screening or selection, and examples for successful applications are shown which enable researchers to choose the most promising tools to solve their protein engineering challenges (see entire publication especially pages 26.7.1- 26.7.10 and Tables 26.7.1, 26.7.2, and 26.7.3).
Chen et al. teach constitutive expression of recombinant human hyaluronidase PH20 in Pichia pastoris. Chen et al. teach a DNA fragment containing core domain of human PH20 gene was cloned into a constitutive expression plasmid (pGAPZαC) of Pichia pastoris to produce a fusion protein with α factor signal in the N-terminus and 6 × His as well as c-Myc tags in the C-terminus, where the resulting plasmid pGAPZαC-PH20 was integrated into the genome of P. pastoris strain GS115. Chen et al. teach that functional recombinant human PH20 (rHuPH20) was successfully expressed and secreted by the recombinant P. pastoris transformant after incubation for 2 days at 30°C; the highest hyaluronidase activity of 2 mU/mL could be obtained at 3 day in an YPD culture; and after purified by phenylboronic acid resin adsorption, rHuPH20 with a specific activity of 230 mU/mg was obtained. See entire publication and abstract especially MATERIALS AND METHODS section, RESULTS AND DISCUSSION section, and pages 674-677.
Frost et al. teach recombinant human hyaluronidase (rHuPH20) where its cDNA was cloned into a well-characterized mammalian cell line. Frost et al. teach that a commercially acceptable expression vector containing the human PH20 cDNA encoding amino acids 1 – 482 (rHuPH20) followed by a cytomegalovirus-driven bicistronic vector with the dihydrofolate reductase (DHFR) selection marker was constructed to allow for positive selection in DHFR-deficient CHO cells previously adapted to grow in chemically defined media without any animal-derived materials. Frost et al. teach that transfectants were cloned in chemically defined media and selected with increasing concentrations of methotrexate to produce a high level rHuPH20-secreting cell line. Frost et al. teach that a four-step column chromatographic downstream purification process was developed that resulted in a highly purified enzyme protein with a specific activity of over 100,000 USP Units/mg protein, where the process resulted in a 447 amino acid 61 kDa glycoprotein with a properly processed amino terminus and 6 N -linked glycosylation sites. See entire publication and abstract especially 2.2 Development of a manufacturing process for rHuPH20 section and pages 432-437.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the teach protein engineering strategies of Bornscheuer et al. on the pH20 hyaluronidase of EP3037529, expressing the modified pH20 hyaluronidase, modify the teachings of EP3037529 to include the methods steps as taught and/or suggested by Chen et al. and Frost et al. for production of the pH20 hyaluronidase or any other PH20 variant including lowering the culture temperature to 28-34 °C. One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do this in order to obtain a simple method for producing and obtaining recombinant pH20 hyaluronidase or variants thereof. It would have been obvious to further modify the teachings of EP3037529 to incorporate the recited culturing steps and/or conditions, and purify the produced PH20 using chromatography recited in the claims as routine experimentation and/or as desired for efficient production of the PH20. One of ordinary skill in the art at the time the invention was made would have a reasonable expectation of success because recombinantly producing PH20 is known in the art as shown by the above reference teachings. Hence, the claimed invention as a whole is prima facie obvious.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US Patent 12221638B2 (02/11/2025; PTO 892). Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims and/or specification of the patents teach the claimed recombinant hyaluronidase PH2O or a variant thereof comprising a substitution of one or more amino acid residues and optionally comprising a deletion of one or more of N-terminal and/or C-terminal amino acid residues in an amino acid sequence of the hyaluronidase PH2O,wherein the hyaluronidase PH2O or variant thereof comprises one or more N-glycan,wherein a sialylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 25%, wherein the sialylation content is a sum of percentage content of N-glycan containing sialic acid,wherein a galactosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 68%, wherein the galactosylation content is a sum of percentage content of N- glycans containing galactose,wherein a mannosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 40 to 63%, wherein the mannosylation content is aa sum of percentage content of N- glycans containing mannose, wherein a sum of the galactosylation content and the mannosylation content is no more than 100%, and wherein an enzymatic activity of the hyaluronidase PH20 or variant thereof is 10,000 units/mL or more. Thus, the teachings anticipate the claimed invention.
Claims 1-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of Application Serial No. 18940064. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims and/or specification of the copending applications teach the claimed recombinant hyaluronidase PH2O or a variant thereof comprising a substitution of one or more amino acid residues and optionally comprising a deletion of one or more of N-terminal and/or C-terminal amino acid residues in an amino acid sequence of the hyaluronidase PH2O,wherein the hyaluronidase PH2O or variant thereof comprises one or more N-glycan, wherein a sialylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 25%, wherein the sialylation content is a sum of percentage content of N-glycan containing sialic acid,wherein a galactosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 1 to 68%, wherein the galactosylation content is a sum of percentage content of N- glycans containing galactose,wherein a mannosylation content of the N-glycan of the hyaluronidase PH2O or variant thereof is 40 to 63%, wherein the mannosylation content is aa sum of percentage content of N- glycans containing mannose,wherein a sum of the galactosylation content and the mannosylation content is no more than 100%, and wherein an enzymatic activity of the hyaluronidase PH20 or variant thereof is 10,000 units/mL or more. Thus, the teachings anticipate the claimed invention.
Conclusion
No claim is allowed.
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/CHRISTIAN L FRONDA/Primary Examiner, Art Unit 1652
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