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
Status of Claims
2. Applicant's preliminary amendment of the instant application, which was originally submitted on 07/20/2023 and later amended on the same day, is acknowledged by the Examiner. The cancellation of claims 2, 3, 5, 7, 8, 12, 17 – 26, and 31 – 34 pursuant to the amendment on 07/20/2023 is acknowledged. Claims 1, 4, 6, 9 – 11, 13 – 16, 27 – 30, and 35 – 40 are pending and under review.
Priority
3. The instant application is a National Stage Entry of International Patent Application No. PCT/US2022/014058 filed on 01/27/2022, which claims priority to U.S. Provisional Application No. 63/144,104 filed on 02/01/2021. Priority is granted to the provisional application for claims 1, 4, 6, 9 – 11, 13 – 16, 27 – 30, and 35 – 40 of the instant application.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 07/20/2023 and 09/12/2023 have been considered by the examiner. Notably, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the Examiner on form PTO-892, they have not been considered. However, all references on the IDS were considered.
Specification
5. Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details. The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
6. The disclosure is objected to because of the following informalities:
Paragraph 00417 recites that both lane 9 and 10 are titers HEK293 cells supplemented with 50 µM copper sulfate. It is interpreted that this is a typographical error and that lane 9 is HEK293 cells supplemented with 5 µM copper sulfate, whereas lane 10 is 50 µM.
Appropriate correction is required.
7. The use of the terms GenBank™ on pages 15, 39, 41, 42, 44, and 123; EX-CELL® on page 38; Fujifilm™ on page 38; Life Technologies™ on page 38; Millipore Sigma™ on page 38, Bac-to-Bac® on page 107; Thermo Fisher Scientific™ on pages 107, 108, 116, 117, 120, and 123; TransIT® on page 108; Insect GeneJuice® on page 108; pFastBac™ on pages 107 and 108; Beckman Coulter™ on page 116, 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 ™, ℠, 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. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
8. 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
9. The drawings are objected to because copper sulfate (CuSO4) is not denoted correctly in Figures 3, 5, and 6. The 4 associated with the oxygen atom of the sulfate group (SO4) should be subscripted in all iterations. 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.
Claim Objections
10. Claims 1, 4, 6, 9 – 11, 13, 14, and 27 – 30 are objected to because of the following informalities:
In claim 1, line 6; claim 4, line 6; and claim 6, line 6, the acronym “VP1” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “VP1” is interpreted to mean “virion protein 1”, as defined on page 1 of the specification. Notably, the recitation of “VP1 protein” is repetitive as the VP1 is already defined as being a protein as part of the abbreviation;
In claim 1, line 5 and claim 6, line 6, the acronym “VP2” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “VP2” is interpreted to mean “virion protein 2”, as defined on page 1 of the specification. Notably, the recitation of “VP2 protein” is repetitive as the VP2 is already defined as being a protein as part of the abbreviation;
In claim 1, line 5; claim 4, line 5; and claim 6, line 6, the acronym “VP3” is recited, but not defined in the claim. An acronym should be defined the first time it appears in an independent claim or in the group of claims under an independent claim. For the purposes of examination, “VP3” is interpreted to mean “virion protein 3”, as defined on page 1 of the specification. Notably, the recitation of “VP3 protein” is repetitive as the VP3 is already defined as being a protein as part of the abbreviation;
There is a typographical error in claim 4, line 6. The period at the end of the sentence should be a semicolon;
There is a typographical error in claim 4, line 9. There is a missing comma after “conditions”, wherein the phrase should read “conditions, but”;
Line 1 of claims 9 – 11, 13, 27 – 30, and 35 – 40 recites the phrase “[T]he method as in claim 1…”. This is grammatically incorrect. It is recommended that all iterations of the phrase read “[T]he method of claim 1…” to be consistent with the phrasing used other claims. Alternative phrasing could be “[T]he method according to claim 1…”;
There is a typographical error in claim 9, line 1. There is a missing comma after “claim 1”, wherein the phrase should read “claim 1, wherein”;
There is a typographical error in claim 11. Copper is listed twice;
There is a typographical error in claim 14, line 2. There is a missing space in the phrase “1nM”, wherein the phrase should read “1 nM”;
Claim 27, line 2 recites the phrase “isolating the rAAV capsid by the host cell.” This is grammatically incorrect. It is recommended that the phrase read “isolating the rAAV capsid from the host cell”;
There is a typographical error in line 1 of claims 27 – 30. There is a missing comma after “claim 1”, wherein the phrase should read “claim 1, further comprising”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC § 112(b)
11. 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.
12. Claims 13, 29, 30, and 35 – 40 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.
13. Claim 13 is vague and unclear, which renders the claim indefinite. Claim 13 recites a Markush group of transition metals, wherein line 12 of the claim recites “sodium bromide and strontium nitrate”. Are sodium bromide and strontium nitrate intended to be kept together? Is having them together pertinent to patentability? Or is this a typographical error? In other words, it is unclear if both of the transition metals are meant to be in the culture medium at the same time, or if they should have been individual chemical compounds in the Markush group. The presence of multiple very different interpretations of the same claim language renders the claim indefinite. In the interest of compact prosecution and in view of the instant specification, it will be inferred that sodium bromide and strontium nitrate are individual chemical compounds in the Markush group and do not have to be jointly present in the culture medium. However, an appropriate amendment is required.
14. Claim 29 is rendered indefinite. Claim 29 recites “the effective amount reduces the concentration of rAAV capsids” in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 1, which claim 29 is dependent upon, recites “the effective amount of the transition metal increases incorporation of VP1, VP2, or VP3 protein into the rAAV capsid” in lines 5 and 6. It is unclear how the transient metal increases incorporation of the proteins into the rAAV capsids, i.e., allows for efficient assembly of the capsids so that they are more potent, as recited in instant claim 1, while simultaneously reducing the yield of the capsids, as defined in instant claim 29. Claim 29 contradicts and lacks antecedent basis with claim 1, which renders the claim indefinite.
15. Claim 30 is ambiguous and unclear, which renders the claims indefinite. Claim 30 recites “the concentration of rAAV capsids is less than a concentration of rAAV capsids produced under the same conditions but being devoid of the effective amount” in lines 3 and 4. There is insufficient antecedent basis for this limitation in the claim. Claim 1, which claim 29 is dependent upon, recites “the effective amount of the transition metal increases incorporation of VP1, VP2, or VP3 protein into the rAAV capsid” in lines 5 and 6. It is unclear how the transient metal increases incorporation of the proteins into the rAAV capsids, i.e., allows for efficient assembly of the capsids, as recited in instant claim 1, while simultaneously reducing the yield of the capsids. Thus, claim 30 contradicts and lacks antecedent basis with claim 1, which renders the claim indefinite.
16. Claims 35 – 40 recite the limitation "the culturing step" in lines 1 and 2. There is insufficient antecedent basis for this limitation in the claim. There is no recitation of “the culturing step” in claim 1, which claims 35 – 40 are dependent upon. However, there is a recitation of “culturing” in claim 1. In the interest of compact prosecution, it will be inferred that “the culturing step” recited in claims 35 – 40 is intended to be the “culturing” in claim 1. However, an appropriate amendment is required.
17. It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this Office Action. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejection(s) and art may be applied in a subsequent Office Action.
35 USC § 112(d)
18. 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.
19. Claim 28 is 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. Claim 28 requires “host cells capable of producing rAAV capsids”. Claim 1, which claim 28 depends on, recites “host cells capable of producing an rAAV capsid” in lines 3 and 4. There are no additional limitations in claim 28 that are not recited in claim 1. Thus, claim 28 fails to further limit the subject matter of claim 1. 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.
35 USC § 112(a)
20. 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.
35 USC § 112(a) – Enablement
21. Claims 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 the tested metal, i.e., copper sulfate, in the tested cell line, i.e., SF9, to increase potency of the rAAV while decreasing its titers, it does not reasonably provide enablement that this phenomenon would work for merely any or cell. 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 use the invention commensurate in scope with these claims.
22. In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit has developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors, to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors considered include (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 in the art; (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.
Breadth of the claims and nature of the invention: Claims 29 and 30 of the claimed invention are drawn to the production of rAAV capsids in a host cell, wherein the addition of a transition metal above its effective amount reduces the concentration of rAAV capsids.
State of the prior art and unpredictability in the art: According to the specification of the claimed
invention, there is a need for new and effective methods and compositions for AAV viral particles (page 2, paragraph 0004). However, in the art, there are numerous methods that can be employed to produced rAAV vectors. Wang, Q., et. al., (A Robust System for Production of Superabundant VP1 Recombinant AAV Vectors. Molecular therapy. Methods & clinical development, 7, 146–156; Published 11/07/2017), hereby Wang, teaches an efficient and scalable suspensions cell culture system for the production of rAAV vectors (page 146, abstract). Galibert, L., et. al., (Origins of truncated supplementary capsid proteins in rAAV8 vectors produced with the baculovirus system. PloS one, 13(11), e0207414; Published 11/15/2018; Cited in Applicant’s IDS on 07/20/2023 as Non-Patent Literature Document Cite No. 2), hereby Galibert, teaches the production of rAAV vectors using the E64 protease inhibitor to prevent degradation of VP1, VP2, and VP3 proteins during culturing (page 1, abstract). Further in the art, Ciccarone, V. C., et. al., (US 2014/0057335 A1; Published 02/27/2014; Cited in Applicant’s IDS on 09/12/2023 as U.S. Patent Document Cite No. 1), hereby Ciccarone, teaches that mammalian cells and transition metals can be added to culturing mediums as a method to increase production of AAV vectors (title and abstract; page 10, paragraph 0088; page 15, paragraph 0119).
To summarize, the prior art, as of 02/01/2021, does not provide evidence for producing lower titers of rAAV vectors with higher potency, but does teach numerous production methods, including those using transition metals and mammalian or insect host cells.
Those with relevant skill in the art: The level of skill in the art is that of Ph.D.–level scientists and
medical doctors (D.O. and/or M.D.).
Amount of direction and existence of working examples: The instant application teaches one working example, which does not represent an example for the innumerable combinations of transition metals and host cells that could be employed to produce rAAV. Thus, the instant application offers no reasonable guidance or direction to use the claimed method for production of rAAV capsids in a host cell, wherein the addition of a transition metal above its effective amount reduces the concentration of rAAV capsids.
The closest working example is in paragraphs 00414 – 00417 on pages 118 – 120, hereby referred to as example 1. Example 1 teaches that decreased titers of rAAV are observed in insect cell cultures, i.e., Sf9 cells, and mammalian cell cultures, i.e., HEK293 cells, as the concentration of copper sulfate was increased. The specification discloses that that although there are decreased concentrations of rAAV, the rAAV capsids that are present have increased potency. It is further taught in the specification that copper sulfate has a dose dependent effect on the potency of novel AAV capsids, wherein those supplemented with copper sulfate had ten-fold higher potency than those without, even though the rAAV titers were lower.
The instant application has no examples of producing rAAV capsids in host cells outside of Sf9 and HEK293 with copper sulfate as the transition metal. There is no guidance as to what properties of the transition metal and host cell may be changed without losing the recited limitation of reduced concentrations of rAAV capsids with higher potency.
Quantity of experimentation needed: The recitation of reduced concentrations of rAAV capsids in a host cell with an effective amount of a transition metal would require undue experimentation due to the unpredictability of production of the rAAV in various host cells and transition metals. In the instantly claimed invention, there would be undue experimentation to individually analyze the ability of all transition metals to decrease the rAAV titers while increasing its potency in all possible host cells. Thus, it is unpredictable as to which combination of transition metals and host cells will yield lower titers of rAAV capsids.
For the reasons discussed above, undue experimentation would be required to practice the claimed invention commensurate with the scope of the claims. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. It would take undue trials and errors to practice the claimed invention in view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims.
Claim Rejections - 35 USC § 102
23. 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
24. Claim 6 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Galibert, L., et. al., (PloS one, 13(11), e0207414; Published 11/15/2018), hereby Galibert.
Galibert teaches the production of rAAV using the E64 protease inhibitor, which is a cysteine protease inhibitor known in the art, as a means to decrease degradation of VP1, VP2, and VP3 (page 1, abstract; page 2, first and second paragraphs; page 3, cell line, baculovirus, and rAAV production; see also definition of E64 protease inhibitor as discussed in International Search Report on 05/05/2022), as defined in instant claim 6. Page 5, third paragraph teaches that there was no truncation of the VP proteins when the cysteine protease inhibitor, i.e., the E64 protease inhibitor, was introduced to the system, correlating with an increased concentration of full-length VP proteins (page 5, third paragraph; page 17, second paragraph), as defined in instant claim 6.
Claim Rejections - 35 USC § 103
25. 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.
26. Claims 1, 4, 11, 13 – 16, 28 – 30, and 35 – 40 are rejected under 35 U.S.C. 103 as being unpatentable over Galibert, and in further view of Ciccarone, V. C., et. al., (US 2014/0057335 A1; Published 02/27/2014), hereby Ciccarone, as evidenced by Wang, Q., et. al., (Molecular therapy. Methods & clinical development, 7, 146–156; Published 11/07/2017), hereby Wang.
Ciccarone teaches efficient and high throughput methods of culture mediums for cell growth and transfection of viruses, including adeno-associated viruses, wherein the volume of the medium is from about one milliliter to 250 liters (title and abstract; page 10, paragraph 0088; page 15, paragraph 0119), as disclosed in instant claims 1, 4, and 35 – 39. It is further taught that a transition metal can be added to the media, wherein the metal is copper, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, zinc, yttrium, zirconium, niobium, molybdenum, technetium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, and mercury (page 8, paragraph 0077), as required in instant claim 11. Ciccarone goes on to teach that the metal can be a salt of copper sulfate, magnesium sulfate, calcium chloride, aluminum chloride, zinc sulfate, sodium sulfate, and numerous others (page 8, paragraph 0069; page 12, paragraph 0106; page 13, paragraph 0108), as required in instant claims 1, 4, and 13.
Ciccarone does not teach the effective concentration of the transition metals, as required in instant claims 14 – 16; or that culturing occurs in a volume of 500 liters or more, as required in instant claim 40. Nonetheless, the culture composition, including the volume of the media and concentration of its components, 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 culture composition, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "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, Ciccarone teaches that culturing can occur in any volume of culture medium, as long as the introduction of the macromolecule occurs in 0.1 to 10 times the amount of medium used to culture cells to be transfected (page 10, paragraph 0088). Page 13, table 1 also teaches the preferred ranges of the salts in grams per liter of media. Thus, culturing occurring in a volume of 500 liters or more is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize, as disclosed in instant claim 40. Moreover, the amount of the transition metal in the media would be dependent on the salt added and culture volume, which one in the art would also routinely optimize, as required in instant claims 14 – 16.
Ciccarone does not teach that the addition of a transition metal to the culture medium results in increased concentrations or incorporation of VP1, VP2, or VP3 into rAAV, as required in instant claims 1 and 4.
However, Ciccarone does teach that increased concentrations of zinc sulfate resulted in increased expression of the virus/vector (page 22, paragraph 0168).
Wang teaches that the expression levels of VP2 and VP3 are proportional to rAAV vector yield (page 149, left column).
It would have been prima facia obvious to one having skill in the art to add zinc sulfate to a culture to increase the yield of rAAV, which would have downstream effects and, thus, increase the concentration of VP2 and VP3 prior to the instant effective filing date. The rationale to modify or combine the prior art may rely on logic and sound scientific principle. In re Soli, 317 F.2d 941, 137 USPQ 797 (CCPA 1963). Moreover, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning).
Ciccarone and Wang are considered to be analogous to the claimed invention because both are drawn to vector production of AAV. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to use the transition metals to increase the concentration of the vector produced by the cells, as taught by Ciccarone, to, in turn, increase the concentration of the VP proteins, as disclosed by Wang. This obviousness is mainly owed to both references teaching culturing, i.e., production, methods of AAV. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Ciccarone and Wang before the effective filing date of the claimed invention with a reasonable expectation of success to have a method that is suitable for large-scale production of rAAV (specification, page 38, paragraph 00123). 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. 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.
27. Claims 9, 10, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Ciccarone and Wang as applied to claims 1, 4, 11, 13 – 16, 28 – 30, and 35 – 40 above, and further in view of Galibert.
Ciccarone and Wang fail to teach the usage of a non-mammalian cell line, i.e., an insect cell, as required in instant claims 9 and 10; and the subsequent isolation of the grown rAAV, as disclosed in instant claim 27.
Galibert teaches that the rAAV is first produced in Sf9 cell cultures, i.e., insect cells, then purified via filtration and affinity chromatography, and analyzed by SDS-PAGE page 1, abstract; page 2, first and second paragraphs; page 3, cell line, baculovirus, and rAAV production; page 4, rAAV purification and characterization), as required in instant claims 9, 10, and 27.
Ciccarone, Wang, and Galibert are considered to be analogous to the claimed invention because all are drawn to vector production. Based on the prior art teachings, it would have been obvious to a person having ordinary skill in the art to use the transition metals to increase the concentration of the vector, as taught by Ciccarone, to, in turn, increase the concentration of the VP proteins, as disclosed by Wang, and produce rAAV in insect cells using the cysteine protease inhibitor as taught by Galibert. This obviousness is mainly owed to all references teaching production methods of vectors, wherein Galibert and Wang specifically teach rAAV. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Galibert, Ciccarone, and Wang before the effective filing date of the claimed invention with a reasonable expectation of success to have a method that is suitable for large-scale production of rAAV (specification, page 38, paragraph 00123). 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. 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
28. Claims 1, 4, 6, 9 – 11, 13 – 16, 27 – 30, and 35 – 40 are rejected. No claims are allowed.
29. 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 7:30-5:30 ET.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Shanon A. Foley/Primary Examiner, Art Unit 1671