Notice of Pre–AIA or AIA Status
1. 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
Priority
2. Acknowledgement is made of applicant’s claim that the instant application is a national stage entry of International Patent Application No. PCT/EP2021/085238 filed on 12/10/2021, which claims priority to United Kingdom Patent Application No. GB2019454.4 filed on 12/10/2020.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 10/31/2023 has been considered by the examiner. The non–patent literature (NPL) referenced as “Joe, C. C. D., et. al. (2022). Manufacturing a chimpanzee adenovirus–vectored SARS–CoV–2 vaccine to meet global needs. Biotechnology and bioengineering, 119 (1), 48–58” has been listed twice on the IDS as Cite No. 8 and 22 under NPL documents. This NPL will only be considered once by the examiner. As such, it has been struck through and not considered with regards to NPL Cite No. 22.
Specification
4. The use of the terms NatriFlo®, Sartobind®, Benzonase®, Pellicon®, Millistak+®, Mustang®, NovaSip™, and possibly others in the specification, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
5. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Drawings
6. The drawings are objected to under 37 CFR 1.84(u)(1), which states "view numbers must be preceded by the abbreviation "FIG.". In the instant case, the view numbers of Figures 1 – 3 are preceded by the word “Figure” or “FIGURE” instead of the abbreviation “FIG.”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
7. The instant application contains at least one drawing executed in color. Figure 2E has parts that refer to and are differentiated by various colors. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the USPTO patent electronic filing system. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Claim Objections
8. Claims 1, 11, 13, 14, and 16 are objected to because of the following informalities:
In claim 1, line 1, there is a missing colon after “comprising”;
In claim 1, line 2, there is a missing semicolon after “adenovirus”;
In claim 1, line 2; claim 13, lines 2 and 3; claim 14, line 2; and claim 15, line 2, the phrase “comprising adenovirus” is grammatically incorrect. More appropriate language would be “comprising the adenovirus”;
In claim 1, line 3, there is a missing semicolon after “filtration”;
In claim 1, line 4, there is a missing semicolon after “of”;
In claim 1, line 5, there is a missing semicolon after “exchange”;
In claim 1, line 6, the phrase “eluting adenovirus” is grammatically incorrect. It is recommended that the phrase read “eluting the adenovirus”;
In claim 11, line 2, there should be a “the” between “comprises” and “use” so that the phrase reads “comprises the use”;
Appropriate correction is required.
Claim Rejections – 35 USC § 112
9. 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.
10. Claims 2 – 4, 9 – 16, and 18 – 25 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.
11. Claims 2 – 4, 9 – 16, and 18 – 25 recite the limitation "a method". There is insufficient antecedent basis for this limitation in the claim. The article “a” is an indefinite term. The article “the” is a definite term and should be used when referring back to the specific method of the previous claim. For example, claim 2 should read “the method according to claim 1” as opposed to “a method according to claim 1”.
12. Claims 4 and 25 contain the trademark/trade name Sartobind®; claims 18 and 19 contain the trademark/trade name Benzonase®; and claim 25 contains the trademark/trade name Mustang®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre–AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a membrane for anion exchange chromatography and, accordingly, the identification/description is indefinite.
13. Claim 22 recites the phrase "preferably", which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. The phrase suggests that the limitation is optional or a preferred embodiment, but is unclear from the claim language itself whether that limitation is essential for infringement or an optional feature. See MPEP § 2173.05(d).
Claim Rejections – 35 USC § 103
14. 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.
15. Claims 1 – 4, 9 – 16, and 18 – 25 are rejected under 35 U.S.C. 103 as being unpatentable over Memarzadeh, B., et. al. (WO 03/078592 A2; Published 09/25/2003; Cited in Applicant's IDS on 10/31/2023, Foreign Patent Document, Cite No. 1), hereby Memarzadeh, as supported by the Benzonase® Nuclease (Published 12/29/2010) and Sartobind® Q and S (Published 12/15/2016) user manuals and in further view of Luitjens, A., et. al. (WO 2011/098592 A1; Published 08/18/2011; Cited in Applicant’s IDS on 10/31/2023, Foreign Patent Document, Cite No. 5), hereby Luitjens; Fedosyuk, S., et. al., (2019), Simian adenovirus vector production for early–phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product–contact components, Vaccine, 37 (47), 6951–6961 (Published 11/08/2019; Cited in Applicant’s IDS on 10/31/2023, NPL Document, Cite No. 4), hereby Fedosyuk; and Folegatti, P. M., et. al., (2020), Safety and immunogenicity of the ChAdOx1 nCoV–19 vaccine against SARS–CoV–2: A preliminary report of a phase 1/2, single–blind, randomized controlled trial, Lancet, 396 (10249), 467 – 478 (Published July 20, 2020), hereby Folegatti.
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Memarzadeh teaches a method for producing and purifying replication competent adenovirus in a single workflow (claim 1; technical field; summary of invention; paragraph 11, lines 1 and 2; see also Figure 1 as reproduced below), wherein host cells infected with said replication competent adenovirus are replicated in suspension (claim 11; paragraph 23, lines 1 – 12), lysed with a detergent (claim 1; cell harvest and lysis), clarified by being passed over a depth filter (claim 1; paragraph 36, lines 1 –11), bound to an anionic exchange filter that is a high throughput filter cartridge (claim 1; separation), and then eluted from the filter at an ionicity of at least 25 mS/cm, which permits separation of the adenovirus from cell contaminants (claim 1; paragraph 42, lines 3 – 7), as recited in instant claims 1, 12 – 14, and 25. It is further taught that the high throughput ion exchange filters are comprised of multiple layers of a filter membrane, and have a bound anion (paragraph 40, lines 1 – 4) that has quaternary amines as the anion exchanger (claim 6), as stated in instant claims 2 and 3. Moreover, it is taught that one or more depth filters of different sizes are sequentially used for clarification with the filters excluding cellular debris, but not the virus particles (paragraph 36, lines 9 – 11; example 2), as required in instant claim 9. While Memarzadeh teaches that the eluant is treated with a nuclease after an initial anion exchange, then refiltered (paragraph 11, lines 5 and 6), it is taught that the nuclease can be added directly to the cell harvest, as defined in claim instant 15, but is more preferably added after the initial purification step to reduce the amount of nuclease needed (Paragraph 70, lines 4 – 7). It is further taught that the nuclease is Benzonase®, a genetically engineered enzyme that has both DNAse and RNAse activity (Paragraph 45, lines 9 – 11; paragraph 70, lines 3 and 4), as stated in instant claims 16 and 18.
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Memarzadeh also teaches that Benzonase® degrades the majority of the DNA in the virus sample within 2 hours at concentrations of 50, 100, and 250 units/mL in comparison to the control of 0 units/mL with no advantage of increasing the concentration beyond 50 units/mL (example 4; see also table 2 as reproduced above). It is further taught that the clarified cell lysate is purified on a Mustang® Q column, wherein the adenovirus is loaded at 40 mS/cm, and eluted at 50 mS/cm in a buffer of 10 mM Tris, 1 mM MgCl2, 500 mM NaCl (example 3; paragraph 65, lines 1 – 3). Memarzadeh does not teach the Benzonase® at a concentration of 15 units/mL, as defined in instant claim 19; or the explicit usage of 20 mM Tris, pH 8 on a Sartobind® Q or Mustang® Q column, as recited in instant claim 25. However, the concentration of Benzonase® and buffer composition is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the concentration of Benzonase® and the buffer composition, including the pH and molarity, needed to achieve the desired results. The principle of law from MPEP §§ 2144.05 states: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). In light of this case law, Memarzadeh does teach that the available capacity of the column is the capacity under particular experiment conditions that include pH and ionic strength (paragraph 37, lines 7 – 9). The Sartobind® Q and S user manual further teaches that process parameters, including the type of buffer, pH, and conductivity, must be controlled to allow the target molecule to bind (section 10, troubleshooting; page 56). Furthermore, the Benzonase® Nuclease user manual teaches that there are several parameters that influence the activity of Benzonase®, wherein the optimal purity/amount of the nuclease and optimal conditions will vary from process to process and thus must be determined experimentally (page 10, frequently asked questions, question 1).
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While Memarzadeh does teach the usage of a Pall Mustang® Q and Sartorius filter cartridge for the anionic exchange filter (claim 7; see also table 4 as reproduced below), it fails to teach that the membrane is explicitly a Sartorius Sartobind® Q membrane, as stated in instant claim 4. However, Luitjens teaches that anionic exchange membranes such as those produced by Pall, i.e., the Mustang® series, and Sartorius, i.e., the Sartobind® series, are suitable to purify adenovirus vectors, as required in instant claim 4.
Memarzadeh and Luitjens fail to teach single–step clarification, as recited in instant claim 10; the usage of a C0SP depth filter during depth filtration, as stated in instant claim 11; buffer exchange via tangential flow filtration (TFF) after anion exchange chromatography, as required in instant claims 20 and 21; and the adenovirus vector being derived from and having the same capsid charge characteristics as ChAdOx1, as defined in instant claims 22 and 24. However, Fedosyuk teaches an in–line process wherein the Millistak+® HC Pro depth filters with C0SP media filters effectively reduce turbidity and are thus a suitable candidate for single–step clarification (results section 3.2, pages 6954, 6955; see also figure 5A from page 6959, as reproduced below), as stated in instant claims 10 and 11. Methods section 2.5 on page 6953 goes on to teach that the eluant is buffer exchanged by means of TFF following ion exchange chromatography, as required in instant claims 20 and 21. It is further taught that one of the eluants is a simian adenovirus vector known as ChAdOx1 that has been modified to express Rift Valley Fever virus (RVF) glycoproteins (methods section 2.2, page 6952; results section 3.1, page 6954), wherein the elution conductivity for ChAdOx1 RVF was 35 mS/cm (results section 3.4, page 6956), as
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defined in instant claims 22 and 24.
Memarzadeh, Luitjens, and Fedosyuk fail to teach that the adenovirus is ChAdOx1 nCoV–19, as stated in instant claim 23. However, Fedosyuk does teach that adenovirus–vectored vaccines targeting diseases, including Middle East Respiratory Syndrome (MERS), have been developed following Good Manufacturing Practice (GMP)–compliant processes, wherein anion exchange resins are commonly employed (introduction, page 6952). Folegatti teaches that they previously developed ChAdOx1 MERS, an adenovirus–vectored vaccine that encodes the spike protein of MERS coronavirus (MERS–CoV), the causative agent of MERS, that was safe and well tolerated in clinical trials (introduction, page 468). It would therefore have been obvious to a person having ordinary skill in the art to apply the ChAdOx1 vector to severe acute respiratory coronavirus 2 (SARS–CoV–2) since both MERS–CoV and SARS–CoV–2 are coronaviruses. In support of this obviousness, Folegatti further teaches that the ChAdOx1 vector model can be modified to contain the full–length SARS–CoV–2 spike protein, i.e., ChAdOx1 nCoV–19 vaccine (AZD1222), that provides protection against SARS–CoV–2 (introduction, pages 468 and 469).
Memarzadeh, Luitjens, Fedosyuk, and Folegatti are considered to be analogous to the claimed invention because all are in the field of adenoviral vectors. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the production and purification method of Memarzadeh, anion exchange column employed in Luitjens, and downstream process including buffer exchange and TFF of Fedosyuk with the ChAdOx nCoV–19 vector in Folegatti and in light of the routine optimization required by the Benzonase® Nuclease and Sartobind® Q user manuals before the effective filing date of the claimed invention to address challenges in manufacturing adenoviral vectors for global vaccine product deployment against SARS–CoV–2 (instant application; page 1, lines 11, 12, 30, and 31). All the claimed elements were known in the prior art. It would have been obvious to a person having ordinary skill in the art to have combined the elements as claimed by known methods with no change in their respective functions. The combination would have yielded nothing more than predictable results to one having ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143A and 2143.02.
Conclusion
16. Claims 1 – 4, 9 – 16, and 18 – 25 are rejected. No claims are allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272–6781. The examiner can normally be reached M–Th 7–5 ET.
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, Janet Andres can be reached at (571)272–0867. The fax phone number for the organization where this application or proceeding is assigned is 571–273–8300.
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/HALLIE N. PENNINGTON, PH.D./
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671