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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Mar. 14, 2025. Claims 1, 7-9, 14-15, 18-20 and 24-27 are pending. Claims 1, 7-9 and 24-27 are currently examined. Claims 14-15 and 18-20 are withdrawn.
Please note: Claims 26-27 are directed to the invention of a non-elected group and are hereby withdrawn.
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.
(New rejection-necessitated by amendment) Claims 1, 7-9 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kwong et al. (US 10017543 B2, patented on Jul. 10, 2018) in view of Ciaramella et al. (US 11,464,848 B2, patented on Oct. 11, 2022, PCT filed on Mar. 15, 2018), Farrell et al. (Anal Chem. 2015 Sep 15;87(18):9186-93), Collins et al. (Curr Top Microbiol Immunol. 2013; 372:3-38). Mundle et al. (Vaccine. 2016 Jul 12;34(32):3690-6) as evidenced by Capto Core 700 (https://www.cytivalifesciences.com/en/us/shop/chromatography/prepacked-columns/multimodal/hitrap-capto-core-700-p-00465) and GE-Capto Core 700 (https://biopharma-asia.com/magazine-articles/the-use-of-capto-core-700-and-capto-q-impres-in-the-purification-of-human-papilloma-virus-like-particles-2/).
The amended base claim 1 is amended to direct an antigen composition comprising a recombinant respiratory syncytial virus (RSV) soluble F protein polypeptide in which amino acids 155, 290, 190 and 207 with reference to the amino acid numbering of SEQ ID NO:1 are 155C, 290C, 190F and 207L, wherein the recombinant RSV soluble F protein polypeptide comprises an F1 chain and an F2 chain wherein the F1 chain comprises an amino acid sequence having at least 95% identity to SEQ ID NO:2 and the F2 chain comprises an amino acid sequence having at least 95% identity to SEQ ID NO:3, wherein the composition comprises greater than 99% recombinant RSV soluble F protein polypeptide w/w versus host-cell protein and wherein the antigen composition comprises less than 0.05% GRP78 host-cell protein w/w versus recombinant RSV soluble F protein polypeptide, wherein the recombinant RSV soluble F protein polypeptide comprises glycan groups, wherein at least 75% of the glycan groups are sialyated, wherein the antigen composition is produced by a process comprising culturing a host-cell comprising a recombinant nucleic acid comprising a polynucleotide sequence that encodes the recombinant RSV soluble F protein polypeptide to express the recombinant RSV soluble F protein polypeptide and subjecting the expressed recombinant RSV soluble F protein polypeptide to a purification process comprising a step of multimodal liquid chromatographic purification utilizing a ligand linked multimodal anion exchange resin and an elution buffer comprising a kosmotropic agent and a chaotropic agent.
Kwong et al. describes the prefusion RSV F proteins and their use, which includes F2 polypeptide and a F1 polypeptide (See e.g. column 55, lines 9-16). It teaches that a respiratory Syncytial Virus (RSV) antigen includes a recombinant RSV F protein stabilized in a prefusion conformation. (See Abstract). Kwong et al. teaches that in several embodiments, the recombinant RSV F protein includes one or more amino acid substitutions that stabilize the protein in the prefusion conformation, for example, that stabilize the membrane distal portion of the F protein (including the N-terminal region of the F1 polypeptide) in the prefusion conformation. In one non-limiting example, the recombinant RSV F protein includes S155C, S290C, S190F, and V207L substitutions (referred to herein as "DSCavl") (See Column 2, lines 38-58). Kwong et al. also teaches that the "isolated" biological component (such as a protein, for example a disclosed PreF antigen or nucleic acid encoding such an antigen) has been substantially separated or purified away from other biological components, such as other biological components in which the component naturally occurs, such as other chromosomal and extrachromosomal DNA, RNA, and proteins. Proteins, peptides and nucleic acids that have been "isolated" include proteins purified by standard purification methods. The term also embraces proteins or peptides prepared by recombinant expression in a host cell as well as chemically synthesized proteins, peptides and nucleic acid molecules. Isolated does not require absolute purity, and can include protein, peptide, or nucleic acid molecules that are at least 50% isolated, such as at least 75%, 80%, 90%, 95%, 98%, 99%, or even 99.9% isolated (See Column 30, lines 47-67).
Although Kwong et al. does not specifically teach the weight (w/w) percentages between the recombinant RSV F protein to the host-cell protein as claimed. Kwong et al. discloses that the isolated antigen does not require absolute purity and can include protein, peptide, or nucleic acid molecules that are at least 50% isolated, such as at least 75%, 80%, 90%, 95%, 98%, 99%, or even 99.9% isolated, where the percentage purity of the isolated antigen composition disclosed in Kwong are at the similar ranges as claimed. Because the recombinant RSV F ( "DSCavl") protein of Kwong is isolated from the host cells, (e.g., 99.9% isolated, which is higher than the claimed 99%), the composition of Kwong would comprise greater than 99% F protein w/w versus host-cell protein, and the composition of Kwong would also comprise less than 0.05% GRP78 host-cell protein w/w versus recombinant RSV soluble F protein polypeptide.
Nonetheless, Farrell et al. teaches that GRP78 is one of the major HCP as the impurities during protein purification process and a mixed-mode chromatograph can remove it to an undetectable level (See (See page 9191, right column, paragraph 1; Table 2, page 9192 and below). Accordingly, it would also be obvious for one of ordinary skill in the art to further purify the F protein, if necessary, to remove GRP78 to undetectable levels or less that 0.05% to produce safe and efficacious therapeutic proteins. One of ordinary skill in the art would be motivated to do so because Farrell et al. teaches that CRP78 is a major HCP impurity that must be removed to produce safe and efficacious therapeutic proteins. There would be a reasonable expectation of success given the teachings and findings of Farrell.
Regarding the limitations of the SEQ ID NO: 1 of soluble F protein, SEQ ID NO:2 of F1 and SEQ ID NO:3 of F2, Ciaramella et al. teaches the SEQ ID NOs 1-3 as follows:
1). Instant SEQ ID NO: 1 is identical to SEQ ID NO: 245 of Ciaramella et al.. (See e.g. column 29, lines 49-54; Table 2 below).
2). SEQ ID NO: 2 is identical to Seq ID NO: 245 of Ciaramella et al. at amino acids 137 aa to 544 aa (See Table 3 below).
3). SEQ ID NO: 3 is identical to Seq ID NO: 245 of Ciaramella et al. at amino acids 26 aa to 109 aa (See Table 4 below). Thus, SEQ ID NO: 245 of Ciaramella et al. comprises each of instant SEQ ID NOs:1-3.
PNG
media_image1.png
878
1228
media_image1.png
Greyscale
PNG
media_image2.png
748
1171
media_image2.png
Greyscale
PNG
media_image3.png
315
1203
media_image3.png
Greyscale
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to select known RSV F protein sequence, including the SEQ ID NO: 245 of Ciaramella, as the F protein comprising the F1 and F2 chain for Kwong to develop the antigen composition as claimed. Because the SEQ ID NO: 245 of Ciaramella has the four mutation amino acids as claimed, one of skill in the art would have been motivated to use the known SEQ ID NO:245 as the RSV soluble F protein, and there would be a reasonable expectation of success to develop and purify an antigen composition comprising the RSV F protein including SEQ ID NO: 1-3 as claimed.
As for the newly added limitation “the recombinant RSV soluble F protein polypeptide comprises glycan groups, wherein at least 75% of the glycan groups are sialyated”, Collins et al. teaches that RSV lacks neuraminidase or hemagglutinin activity and the F protein is known to be heavily sialylated, presumably because of the lack of a neuraminidase (See page 2, paragraph 4), at the same time, the instant claims do not recite a modification that affects/induces more glycosylation/sialyation. Accordingly, since Kwong et al. teaches a same F construct as claimed, the glycosylation percentage of F protein of Kwong should be comparable to the claimed RSV F protein.
As for the newly amended base claim 1 at “antigen composition”, “a ligand linked multimodal anion exchange resin” and “an elution buffer comprising a kosmotropic agent and a chaotropic agent”, Kwong et al. teaches that the antigen composition of RSV soluble F protein is produced by a process of transfecting the HEK293 cells (See e.g., column 165, lines 23-40) and a purification with an elution buffer consisting of 20 mM Tris-HCl pH 7.5, 200 mM NaCl, and 250 mM imidazole pH 8.0 (See e.g., column 165, lines 41-55), where the NaCl is a kosmotropic agent and the 250 mM imidazole is a chaotropic agent. However, Kwong et al. uses the NTA resin and StrepTactin resin for RSV soluble F protein purification (See column 165, lines 25-55) that is different from the ligand linked multimodal anion exchange resin as required in the instant base claim 1.
Mundle et al. teaches a Chromatographic separation of RSV virions from contaminating host cell proteins using Capto Core 700 column (See page 3691, paragraphs 2 and 4), where the Capto Core 700 is a multimodal chromatography resin that combines size-exclusion and mixed-mode anion exchange properties containing octylamine ligands that are both positively charged (anion exchange) and hydrophobic, which can be evidenced by Cytiva-Capto core 700 (https://www.cytivalifesciences.com/en/us/insights/multimodal-chromatography). Cytiva discloses that Capto core 700 is one of the multimodal chromatography with a ligand-linked resin, and is mixed-mode anion exchange characteristics (See page 2, paragraph 2), which teaches the claimed multimodal liquid anion chromatographic exchanges as claimed. Mundle et al. further teaches that Capto Core 700 (GE Healthcare Life Sciences) is a novel, core bead technology-based resin that combines size separation and binding chemistry in a single matrix, with the promise of improved process productivity for the production of large molecules such as viruses and their results, and demonstrate that the core bead resin approach can be used to prepare highly-purified RSV that is of similar potency to crude, unpurified material when tested in vivo (See page 3691, left column, paragraph 1).
At the same time, GE teaches that the HPV L1 protein can be purified using Capto Core 700 and Capto Q ImpRes. Capto Core 700 offers effective separation by size, where VLPs are allowed to pass in the flowthrough, whereas impurities are captured in the core of the beads. In the second anion exchange step, L1 protein from disassembled VLPs is captured on Capto Q ImpRes medium. Elution of the target protein from Capto Q ImpRes resulted in a highly purified L1 protein (See page 6, Conclusion). Using the combination purification steps with Capto Core 700 and Capto Q ImpRes, the glycoprotein L1 of HPV can be acquired at 99% purity (See page 6, paragraph 1).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to apply the Capto core 700 into Kwong’s study to arrive at an invention as claimed. Based on the description above, Mundle teaches a high purity RSV being purified using Capto core 700 that is a multimodal resin with both a positively charged (anionic) and a hydrophobic component. GE teaches using Capto Core 700 and Capto Q ImpRes to purify the glycoprotein L1 of HPV to reach a 99% high purity. Therefore, one of skill in the artwould have been motivated to use Capto Core 700 and another anion resin like Capto Q ImpRes to purify the F protein of RSV to reach a high purity as claimed, where the F protein and L protein are both viral glycoproteins. There would be a reasonable expectation of success to develop such a method comprising a step of multimodal liquid chromatographic purification to purify the soluble F protein of RSV based on the teachings of Kwong, Mundle and GE.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Regarding claim 7, it requires the antigen composition is lyophilized. Kwong et al. teaches that in particular embodiments, suitable for administration to a subject the carrier may be sterile, and/or suspended or otherwise contained in a unit dosage form that may be lyophilized for subsequent solubilization and administration (See Column 35, lines 5-10).
Regarding claims 8 and 9, it requires that an immunogenic composition comprising an antigen composition of claim 1 and a pharmaceutically acceptable carrier or excipient (Claim 8) and further comprising an adjuvant (Claim 9). Kwong et al. teaches that compositions including the Pre F antigens. The composition may be a pharmaceutical composition suitable for administration to a subject, and may also be contained in a unit dosage form. Kwong et al. also teaches that an immunogenic composition comprising an effective amount of the immunogen of recombinant RSV F protein and a pharmaceutically acceptable carrier (See e.g. Claim 30, column 282).
Regarding claims 24-25, Kwong et al. teaches that a recombinant protein is encoded by a heterologous (for example, recombinant) nucleic acid that has been introduced into a host cell, such as a bacterial or eukaryotic cell. The nucleic acid can be introduced, for example, on an expression vector having signals capable of expressing the protein encoded by the introduced nucleic acid or the nucleic acid can be integrated into the host cell chromosome (See column 36, lines 1-9), for example, example 5 shows that the polynucleotide sequence encode the RSV soluble F protein (See column 178).
Responses to Applicant’s Remarks
Applicant’s arguments filed on Aug. 29, 2025 have been received and fully considered.
Applicant’s argument on the rejection Under 35 U.S.C. §103 are not found persuasive based on the following:
1). Applicant argued that the cited references failed to teach every
element of amended claim 1 (See Remarks, page 6).
The argument is not persuasive.
Based on the rejection above, the new cited references of Mundle and GE teaches the amended base claim 1.
2). Applicant argued the level of purity of claim 1 (See Remarks, page 6).
The argument is not persuasive.
For the argument of less than 0.05% GRP78 host-cell protein, it was already addressed in the action filed on May 06, 2025.
For the argument on the level of purity of the amended claim 1 (greater than 99% RSV soluble F protein w/w versus host-cell protein), the newly cited referencesteach that their purification method comprising the application of Capto core 700 can remove ≥99% of the Vero HCP and ∼95% of the residual Vero DNA. Importantly, similar yield and purification factor are achieved with preparation of different strains (WT MSA1 and LAV) of RSV (See Mundle et al. page 3695, left column, paragraph 4). Also, GE teaches that their purification method comprising the application of Capto core 700 can reach over 99% purity in the L1 protein purification. It would be obvious for one of ordinary skill in the art to modify a F protein of RSV separation steps to reach a high purity yield as claimed through routine experimental optimization.
3). Applicant argued that the purity levels achieved in claim 1 are not routine or obvious. Rather, the process requires the use of a chromatography step in which the elution buffer comprises a chaotropic agent and kosmotropic agent (see Remarks, page 6).
The argument is not persuasive.
Based on rejection above, Kwong teaches using the chaotropic agent (such as imidazole) and kosmotropic agent (such as NaCl) in the elution steps. Nevertheless, Mundle teaches using a multimodal chromatography (Capto core 700) to purify the RSV virus and GE teaches using Capto core 700 and another anion resin such as Capto Q ImpRes to purify a viral glycoprotein. It would be obvious for one of ordinary skill in the art to test a method to purify F protein of RSV using a multimodal chromatography purification including multimodal anion exchange resin. Based on the teaching of Mundle and GE, modifying a method to purify F protein of RSV from the L protein of HPV can be considered as a routine experiment.
4). Applicant’s argument regarding the invention of WO2014/160463 and the “75% of the glycan groups are sialyated” (See Remarks, pages 7 and 8) were already address in the action filed on May 06, 2025.
5). Applicant argued that the inventors of the present disclosure surprisingly found that the RSV F protein polypeptide of the present disclosure comprises much lower amount of partial glycosylation and displays over 75% of sialyated glycans with the Example 3 C. and Example 3 E., pages 81-83 (See Remarks, page 7).
The argument is not persuasive. Applicant has not provided any evidence to support the unexpected results.
Also, as an initial matter, “the burden of showing unexpected results rests on one who asserts them. Thus, it is not enough to show that results are obtained which differ from those obtained in the prior art: that difference must be shown to be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA 1972) (citation omitted). Moreover, “[i]t is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements in the specification does not suffice.” In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984) (citation omitted).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-5:00 pm, EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached on (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RUIXUE WANG/ Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672