DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ arguments, filed 03/23/2026, have been fully considered. Rejections and/or objections not reiterated from previous office action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Newly submitted claims 79-81 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: Invention originally elected and the invention of claims 79-81 are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case the instantly claimed product of the originally elected invention can be used to treat an oncological order.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 79-81 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Claim Rejections - 35 USC § 103 – New by Amendment
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
1) Claims 1, 8, 12, 14, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over McCook et al. (US 2008/0233183 A1; publication date 09/25/2008; cited in IDS 08/02/2024) in view of Okada et al. (WO 2006/099169 A2, publication date 09/21/2006) and Wei (CN 101480381 A, publication date 07/15/2009; citing English machine translation).
McCook provides compositions suitable for intravenous delivery of lipophilic bioactive agents [abstract & 0074], such as Coenzyme Q10 (i.e., instant claim 6) [0020]. McCook discloses the compositions may include bioactive agents encapsulated in liposomes, and that solubilizers may be employed to aid their encapsulation [0022]. According to McCook, poloxamers (i.e., opsonization reducer according to instant claim 4) are suitable solubilizers [0023]. Finally, McCook discloses that the liposomes are less than 600 nm [0035], the compositions may comprise water as a carrier (i.e., an aqueous solution) [0006] and the compositions may be formulated as emulsions (i.e., dispersion according to instant claim 8) [0045]. McCook does disclose that any phospholipid and/or phospholipid derivative may be utilized to form a liposome for encapsulating the lipophilic bioactive agent (i.e., Coenzyme Q10) [0015]. McCook teaches a concentrate of the compositions [0031] and discloses the bioactive, i.e., coenzyme Q10, “may be present in the resulting concentrate in an amount of from about 10% by weight of the concentrate to about 30% by weight of the concentrate, … The amount of phospholipids in the concentrate may be from about 1% by weight of the concentrate to about 20% by weight of the concentrate” (i.e., weight ratio of active to phospholipid of 30:1 to 10:20; e.g., 16:12 or 4:3) [0037]. McCook further discloses the concentrate comprises water and the solubilizer [0037].
McCook does not disclose dimyristoylphosphatidyl choline (DMPC) and poloxamer 188.
Weight per volume ratio of claim 1 is interpreted to mean a weight ratio because in solution the volume in the denominator of each component in the ratio would be the same.
Okada “relates to novel lipid-containing compositions (including liposomes (e.g., targeted liposomes, blank liposomes), lipid mixtures and liposome-containing compositions) that may optionally incorporate a drug” [0030]. Okada discloses these compositions may also be suitable for intravenous administration [0103]. Okada teaches that DMPC is a particularly suitable phospholipid to form the liposomes [0123]. According to Okada the liposomes may range in size from 50 nm to 250 nm (i.e., less than 600 nm) [0124]. DMPC is defined by Okada to be dimyristoyl phosphatidylcholine [0249].
Okada does not disclose poloxamer 188.
Wei discloses “a kind of coenzyme Q 10 pharmaceutical composition, comprise: (1) is active component with the coenzyme Q10, (2) be solubilizing agent with in … poloxamer (poloxamer), … (4) with water for injection be solvent” (emphasis added) [p. 6 para. 2]. Wei also discloses the poloxamer solubilizing agent is preferably poloxamer 188 [p. 7, para 1].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected DMPC as the phospholipid desired by McCook because Okada discloses it as a suitable option. One would have had an expectation of success because McCook desires any phospholipid to form a liposome and Okada discloses DMPC is particularly suitable to form liposomes.
Similarly, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected poloxamer 188 as the poloxamer solubilizing agent desired by McCook because Wei discloses poloxamer 188 is a preferred solubilizing agent for Coenzyme Q10.
With respect to the claimed ratio of coenzyme Q10 to DMPC, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed ratio of CoQ10 to DMPC of 4:3 lies inside the range of the prior art (i.e., active to phospholipid of 30:1 to 10:20; e.g., 16:12 or 4:3) and so a prima facie case of obviousness exists.
With respect to the ratio of poloxamer 188 to CoQ10, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated the compositions of McCook to comprise Coenzyme Q10 and poloxamer 188 at the instantly claimed ratios through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In the present case, the prior art teaches a composition comprising Coenzyme Q10 and DMPC at a 4:3 weight ratio, and further comprising solubilizer (i.e., poloxamer 188), in the same context as instantly claimed. One of ordinary skill in the art would have been motivated to optimize the composition disclosed by McCook because of the “normal desire of scientists to improve upon what is already generally known”. Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382. Please refer to MPEP 2144.05). A skilled artisan would have been motivated to optimize the amount of solubilizer in composition for optimal solubilizing effect to aid in the encapsulation of the active, as desire by McCook. On would have had an expectation of success because McCook discloses poloxamer solubilizers may be used to aid encapsulation of active agents.
Finally, a prima facie case of obviousness exists for the particle size recited in instant claims 1, 14 and 18 (less than 200 nm, 10-200 nm and less than 45 nm, respectively) because they overlap with the range of the prior art (less than 600 nm). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a composition for intravenous administration comprising Coenzyme Q10, DMPC and poloxamer 188 at the instantly claimed ratios. Wherein the composition is in the form of a nano-liposomal emulsion (dispersion), and the liposomes are made to have a mean particle size within the instantly claimed ranges.
Regarding instant claim 12, McCook discloses that the concentrate “may permit tailoring the production of various compositions having the bioactive agent at varying concentrations” [0068]. McCook also discloses Coenzyme Q10 may be present in amounts from 0.5 to 20% by weight [0071].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have diluted the concentrate taught by McCook, Okada and Wei to comprise 4% coenzyme Q10 because McCook discloses that is a suitable concentration of coenzyme Q10. See MPEP 2143, Exemplary Rationale A.
In making this dilution the composition would have also comprised 3% DMPC and 0.5-1.5% poloxamer 188 because, as discussed above, the concentrate comprised CoQ:DMPC:poloxamer 188 at a ratio of 4:3:0.5-1.5. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). In the present case, the instantly claimed weight-per-volume percent ranges of the instant claims overlaps with the ranges of the prior art and so a prima facie case of obviousness exists.
2) Claim 10 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over McCook et al. (US 2008/0233183 A1; publication date 09/25/2008; cited in IDS 08/02/2024) in view of Okada et al. (WO 2006/099169 A2, publication date 09/21/2006) and Wei (CN 101480381 A, publication date 07/15/2009; citing English machine translation) as applied to claims 1, 8, 12, 14, and 19 above, and further in view of Anderson et al. (US 6,403,116, date of patent 06/11/2002; cited in IDS 08/02/2024).
McCook, Okada and Wei, which are taught above, differ from the instant claims insofar as they do not disclose a Coenzyme Q10 in a crystalline form or a super-cooled melt form.
Anderson discloses the Co-Q10 (i.e., Coenzyme Q10) is crystalline at room temperature and has a melting point of 49 deg C [col. 1, line 36].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have used Coenzyme Q10 in its standard crystalline form since, at the time of filing, it was known that Co-Q10 exits in crystalline form at room temperature and has a melting point of 49 deg C, as taught by Anderson.
3) Claim 20, 22 and 23 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over McCook et al. (US 2008/0233183 A1; publication date 09/25/2008; cited in IDS 08/02/2024) in view of Okada et al. (WO 2006/099169 A2, publication date 09/21/2006) and Wei (CN 101480381 A, publication date 07/15/2009; citing English machine translation) as applied to claims 1, 8, 12, 14, and 19 above, and further in view of Betageri et al. (International Journal of Pharmaceutics, 1992, vol. 81, p. 235-241).
McCook, Okada and Wei, which are taught above, differ from the instant claims insofar as they do not teach multilamellar liposomes and encapsulating a hydrophilic agent.
Betageri relates to the drug encapsulation and release from multilamellar liposomes [title]. Specifically, “[t]he encapsulation of propranolol, a lipophilic drug, and atenolol, a hydrophilic drug, was measured in liposomes of various lipid composition. In addition, release characteristics from multilamellar and unilamellar liposomes were studied” [p. 236, right col., first para.]. Betageri discloses multilamellar liposomes may encapsulate both hydrophilic drugs [p. 237, Table 1] and hydrophobic drugs [p. 237, Table 2]. Betageri also teaches that hydrophilic drugs are encapsulated into the aqueous spaces, the hydrophobic drugs are incorporated into the lipid membrane and the release rate of both drugs can be altered by changing the number of bilayers of the liposomes [p. 240, final para.].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have modified the general teaching of liposomes in McCook with the disclosure of multilamellar liposomes in Betageri. One would have been motivated to form the liposomes of McCook as multilamellar liposomes to provide a means to alter the release rate of the encapsulated drug. One would have had an expectation of success because Betageri discloses that multilamellar liposomes are useful for encapsulating drugs and by changing the number of bilayers one may alter the release rate. It also would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the elements of the prior art to form a multilamellar liposome which encapsulates both a hydrophilic and hydrophobic agent. One would have been motivated to do so in order to deliver two drugs at once. One would have had an expectation of success because Betageri discloses multilamellar liposomes may encapsulate hydrophilic and hydrophobic drugs in different parts of the liposomes. In combining these elements, one would have expected nothing more than predictable results because, when combined, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to formulated the liposomal Coenzyme Q10 composition taught by McCook to comprise multilamellar liposomes with hydrophilic agents encapsulated in the aqueous spaces between bilayers and the hydrophobic active agent (Coenzyme Q10) entrapped within the lipophilic bilayers.
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1) Claims 1, 8, 10, 12, 14, 19-20, 22, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 8,454,945 B2 in view of McCook et al. (US 2008/0233183 A1; publication date 09/25/2008; cited in IDS 08/02/2024), Anderson et al. (US 6,403,116, date of patent 06/11/2002; cited in IDS 08/02/2024), Okada et al. (WO 2006/099169 A2, publication date 09/21/2006), Wei (CN 101480381 A, publication date 07/15/2009; citing English machine translation) and Betageri et al. (International Journal of Pharmaceutics, 1992, vol. 81, p. 235-241).
The claims of ‘945 disclose a composition comprising a phospholipid liposome, Coenzyme Q10 and at least on solubilizer [claim 1] wherein the pharmaceutically acceptable carrier is water (i.e., aqueous) [claim 14].
McCook discloses poloxamers are suitable solubilizers for liposomal Coenzyme Q10 [0023]. McCook also discloses emulsions are suitable formulations for liposomal compositions of Coenzyme Q10 [0045]. McCook discloses that the liposomes are less than 600 nm [0035].
Okada “relates to novel lipid-containing compositions (including liposomes (e.g., targeted liposomes, blank liposomes), lipid mixtures and liposome-containing compositions) that may optionally incorporate a drug” [0030]. Okada discloses these compositions may also be suitable for intravenous administration [0103]. Okada teaches that DMPC is a particularly suitable phospholipid to form the liposomes [0123]. According to Okada the liposomes may range in size from 50 nm to 250 nm [0124]. DMPC is defined by Okada to be dimyristoyl phosphatidylcholine [0249].
Wei discloses “a kind of coenzyme Q 10 pharmaceutical composition, comprise: (1) is active component with the coenzyme Q10, (2) be solubilizing agent with in … poloxamer (poloxamer), … (4) with water for injection be solvent” (emphasis added) [p. 6 para. 2]. Wei also discloses the poloxamer solubilizing agent is preferably poloxamer 188 [p. 7, para 1].
Anderson discloses the Co-Q10 (i.e., Coenzyme Q10) is crystalline at room temperature and has a melting point of 49 deg C [col. 1, line 36].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected DMPC, poloxamer 188 and crystalline Coenzyme Q10 as the phospholipid, solubilizer and Coenzyme Q10 desired by the claims of ‘945 and formulated the composition as an emulsion because the prior art discloses them as a suitable options.
Furthermore, Finally, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated a composition comprising Coenzyme Q10, DMPC and poloxamer 188 in the instantly claimed weight per volume amounts through routine optimization. It has been held that it is not inventive to discover the optimum workable ranges by routine experimentation where, as is here, the general conditions of the claim are disclosed in the prior art. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In the present case, the claims of ‘945 and the prior art disclose composition comprising Coenzyme Q10, DMPC and poloxamer in the same context (i.e., an aqueous nano-dispersion of a hydrophobic acid agent suitable for intravenous administration) as instantly claimed. McCook also provides a starting point for optimization insofar as McCook discloses suitable weight percent ranges. One of ordinary skill in the art would have been motivated to optimize the composition disclosed by the claims of ‘945 and the prior art because of the “normal desire of scientists to improve upon what is already generally known”. Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382. Please refer to MPEP 2144.05). Additionally, one of ordinary skill in the art would have been motivated to optimize the composition disclosed by the claims of ‘945 and the prior art, with respect to a weight-per-volume percent, because the composition is an emulsion of solid particles (liposomal Coenzyme Q10) in a liquid carrier (water).
Betageri discloses multilamellar liposomes may encapsulate both hydrophilic drugs [p. 237, Table 1] and hydrophobic drugs [p. 237, Table 2]. Betageri also teaches that hydrophilic drugs are encapsulated int the aqueous spaces, the hydrophobic drugs are incorporated into the lipid membrane and the release rate of both drugs can be altered by changing the number of bilayers of the liposomes [p. 240, final para.].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have modified the general teaching of liposomes in the claims of ‘945 with the disclosure of multilamellar liposomes in Betageri. One would have been motivated to do form the liposomes of the claims of ‘945 as multilamellar liposomes to provide a means to alter the release rate of the encapsulated drug. One would have had an expectation of success because Betageri discloses that multilamellar liposomes are useful for encapsulating drugs and by changing the number of bilayers one may alter the release rate. It also would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the elements of the prior art to form a multilamellar liposome which encapsulates both a hydrophilic and hydrophobic agent. One would have been motivated to do so in order to deliver two drugs at once. One would have had an expectation of success because Betageri discloses multilamellar liposomes may encapsulated hydrophilic and hydrophobic drugs in different parts of the liposomes. In combining these elements, one would have expected nothing more than predictable results because, when combined, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
2) Claims 1, 8, 10, 12, 14, 19-20, 22, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 10,376,477 B2 in view of McCook et al. (US 2008/0233183 A1; publication date 09/25/2008; cited in IDS 08/02/2024), Anderson et al. (US 6,403,116, date of patent 06/11/2002; cited in IDS 08/02/2024) and Betageri et al. (International Journal of Pharmaceutics, 1992, vol. 81, p. 235-241)
The claims of ‘477 teach an aqueous composition comprising CoQ10 (i.e., Coenzyme Q10) dispersed into a nano-dispersion of particles, at least one of a dispersion stabilizing agent and an opsonization reducer, wherein the nano-dispersion of the CoQ10 is dispersed into nano-particles having a mean particle size of less than 200-nm [claim 16]. Wherein the CoQ10 formulation has a weight-per-volume of the CoQ10, DMPC and poloxamer 188 of 4%, 3% and 1.5%, respectively [claim 22].
The claims of ‘477 do not disclose an emulsion, crystalline CoQ10.
McCook also discloses emulsions are suitable formulations for liposomal compositions of Coenzyme Q10 [0045].
Anderson discloses the Co-Q10 (i.e., Coenzyme Q10) is crystalline at room temperature and has a melting point of 49 deg C [col. 1, line 36].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have selected crystalline Coenzyme Q10 as the Coenzyme Q10 desired by the claims of ‘477 and formulated the composition as an emulsion because the prior art discloses them as a suitable options.
The claims of ‘477 McCook and Anderson do not disclose a multilamellar liposome.
Betageri discloses multilamellar liposomes may encapsulate both hydrophilic drugs [p. 237, Table 1] and hydrophobic drugs [p. 237, Table 2]. Betageri also teaches that hydrophilic drugs are encapsulated int the aqueous spaces, the hydrophobic drugs are incorporated into the lipid membrane and the release rate of both drugs can be altered by changing the number of bilayers of the liposomes [p. 240, final para.].
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have modified the general teaching of liposomes in the claims of ‘477 with the disclosure of multilamellar liposomes in Betageri. One would have been motivated to do form the liposomes of the claims of ‘477 as multilamellar liposomes to provide a means to alter the release rate of the encapsulated drug. One would have had an expectation of success because Betageri discloses that multilamellar liposomes are useful for encapsulating drugs and by changing the number of bilayers one may alter the release rate. It also would have been obvious to one of ordinary skill in the art, at the time of filling, to have combined the elements of the prior art to form a multilamellar liposome which encapsulates both a hydrophilic and hydrophobic agent. One would have been motivated to do so in order to deliver two drugs at once. One would have had an expectation of success because Betageri discloses multilamellar liposomes may encapsulated hydrophilic and hydrophobic drugs in different parts of the liposomes. In combining these elements, one would have expected nothing more than predictable results because, when combined, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Response to Arguments
1) On page 8 of their Remarks, Applicant argues that McCook cannot render the amended clams 1 and 19 obvious because it does not discloses DMPC and poloxamer 188.
This argument is moot in view of the new grounds for rejection necessitated by amendment.
2) On page 8 of their Remarks, Applicant argues that Anderson fails remedy McCook because Anderson fails to teach CoQ10, DMPC and poloxamer 188.
This argument is not persuasive. Anderson is relied on to render the state of CoQ10 obvious, not the composition of the liposome.
3) On pages 10-11 of their Remarks, Applicant argues that McCook does not teach the instantly claimed weight per volume percents of CoQ10, DMPC and poloxamer 188. “Applicant submits that paragraph [0029] of McCook, which is cited in the Office Action, teaches that ‘the phospholipid may be present in an amount of from about 1% by weight to about 20% by weight of the combination of phospholipid, solubilizer, and lipophilic bioactive agent’. In contrast, the claim 12 requires that the DMPC is present at an amount of 35% by weight of the combination of DMPC, poloxamer 188 and CoQl0.” (see Remarks at page 11, first paragraph).
This argument is moot in view of the new rejections necessitated by amendment. In addressing the newly amended weight-per-volume ratios (i.e., weight ratios) of instant claims 1 and 19, the Examiner has cited paragraph 37 of McCook which is directed to a concentrate and discloses concentrations with respect to the weight of the concentrate.
4) On page 11 of their Remarks, Applicant argues “McCook teaches that the weight ratio of lipophilic bioactive agent to solubilizer ranges from ‘about 1:1 to about 4:2.’ (see, paragraph [0025] of McCook). In contrast, the present claim requires 4% of CoQ10 and 1.5% poloxamer 188, or 8% CoQ10 and 3% poloxamer 188.”
This argument is not persuasive. As discussed above, a skilled artisan would have been motivated to optimize the amount of solubilizing agent in the concentrate composition of McCook. The disclosed lipophilic bioactive agent to solubilizer range of 1:1 to about 4:2 of McCook overlaps with the instantly claimed range of 4:0.5 to 4:1.5 and so it would have only supported a skilled artisan in reaching the instantly claimed range through routine optimization.
5) On pages 11-12 of their Remarks, Applicant argues “one of ordinary skill in the art would not have been motivated, nor have reasonably expected, based on the teachings of McCook, Millipore, Okada and Wei, each alone or in combination, to arrive in a predictable manner at the claimed formulation for intravenous administration comprising coenzyme Q 10 (CoQ 10), dimyristoylphosphatidyl choline (DMPC), and poloxamer 188 at the recited amounts.”
This argument is not persuasive. Okada relates to the same subject matter as the instant application and McCook because it discloses a liposomal drug delivery system (Okada at [abstract]). Okada teaches that DMPC is a particularly suitable phospholipid to form the liposomes [0123] and so a skilled artisan would have been motivated to, and had an expectation of success in using DMPC for the liposomal drug delivery in McCook. Wei relates to compositions for injection of coenzyme Q10 and discloses that poloxamer 188 is a preferred solubilizing agent (Wei at [p. 7, para 1]). Thus, a skilled artisan would have been motivated and had an expectation of success in selected poloxamer 188 of the poloxamer solubilizing agent desired by McCook for the compositions of coenzyme Q10 intended for injection disclosed therein.
6) On page 12 of their Remarks, Applicant argues that Tables 1-3 (page 37) and Examples 1-11 (pages 56-59) of the instant specification demonstrate the amounts for the hydrophobic agent, the stabilizing agent and the opsonization reducer provide the unexpected property of producing colloidal CoQ10 particles having sizes below 200 nm, remaining stable at room temperature over several weeks, remaining stable after dilution with saline solution, and which are suitable for intravenous administration.
This argument is not persuasive. The instant specification, as originally filed, does not appear to discloses that the weight ratios provide unexpected results.
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (MPEP 716.02(b)). In the present case the tables do not support a result which is statistically significant. Table 1 demonstrates that formulations with ratios outside the scope of the instant claims (e.g., ratio of 4/1/1) and even compositions which do not comprise a poloxamer (e.g., ratio of 4/1/0) are able to form liposomes with a diameter less than 200nm. Table 2 reveals that compositions without poloxamer 188 (i.e., ratio of 4:3:0; “0494-01-41” row 1) demonstrate the same stability as the inventive compositions (i.e., ratio 4:3:1.5; “0494-01-44” row 2) over several weeks, from about 9/25/09 to 10/19/09. “Table 3 presents the stability results. Time dependent particle size increase was observed in both saline diluted and undiluted samples. From "0 hrs" to "48 hrs" the particle size increased by 5-8-nm for the 4:3:0 formulation and by 10-11-nm for the 4:3:1.5 formulation” (instant specification at paragraph [0174]). Thus, in view of Table 3, a skilled artisan would have understood that the comparative examples are more stable than the inventive examples because the comparative examples demonstrate smaller size changes. Examples 1-10 describe the preparation of the samples in Tables 1-3.
Example 11 compares the plasma concentration over times after administering compositions comprising poloxamers (formulation 2) and compositions without poloxamers (formulation 1). However, the Examiner is unable to find any indication as to the makeup of formulations 1 and 2. Therefore, the examiner can not make a determination on the unexpectedness of the results because the compositions have not been disclosed.
The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support" (see MPEP 716.02(d) quoting In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)). In the present case, the results of claims and example 11 cannot be commensurate in scope because the formulations of example 11 are not disclosed.
7) On page 12 of their Remarks, Applicant argues unexpected pharmacokinetics. Examples 11 and 19-23 describe the determination of pharmacokinetic (PK) properties and toxicology studies of CoQ 10 formulations of the disclosure. The results demonstrate an increase of PK parameters Cmax and AUCo-t with increasing COQ10 formulation dose, uptake of CoQ10 by tissues such as liver and lung, safe plasma profiles, and no adverse effects on clinical observations, ophthalmology, hematology, or urinalysis parameters.
This argument is not persuasive. The instant specification, as originally filed, does not appear to discloses that the weight ratios provide unexpected results. Furthermore, the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (MPEP 716.02(b)). In the present case the results of example 11 do not appear to be unexpected. For example, at the end of example 11 at paragraph 252 on page 65 of the instant specification:
“The results of this study demonstrate a greater accumulation of Coenzyme Q 10 in the liver and spleen for Formulation 1, which does not comprise poloxamer, as compared to Formulation 2, which comprises poloxamer. These results indicate a greater clearance of Coenzyme Q 10 from the blood by the liver and spleen in the absence of poloxamer, and less clearance of Coenzyme Q 10 from the blood by these organs in the presence of poloxamer, and are consistent with the role of poloxamer in the Coenzyme Q 10 formulations as an opsonization reducer.”
Therefore, a skilled artisan would have expected the results demonstrated by example 11 because they “are consistent with the role of poloxamer in the Coenzyme Q 10 formulations as an opsonization reducer.”
The "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support" (see MPEP 716.02(d) quoting In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)). In the present case, the results of claims and example 11 cannot be commensurate in scope because the formulations of example 11 are not disclosed.
8) On pages 12-13 of their Remarks, Applicant argues examples 12-18 demonstrate unexpected results of the instant formulations.
This argument is not persuasive. The instant specification does not appear to discloses the instant formulations provide unexpected results.
With respect to examples 12-14 and 16-18, “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. See MPEP 2112(I).
Example 12 (paragraphs 253-256, page 65-66) compares the effect of blank compositions, inventive compositions, cyclophosphamide compositions and inventive composition + cyclophosphamide compositions on liver cancer. That is to say the evidence only compares blanks, the inventive composition and a different active agent. The same is true of example 14 (paragraphs 258-261, p. 67), example 16 (paragraphs 276, page 71), example 17 (paragraphs 278-279, p. 72). Example 13 (paragraphs 257, p. 66) relates to the dosing rates of coenzyme Q10 in inventive compositions, not the formulations of the compositions. Example 18 does not disclose an inventive formulation, rather it describes the effects of coenzyme Q10. As such, the comparisons disclosed in examples 12-14 and 16-18 only demonstrate the inherent effect of coenzyme Q10, rather than unexpected results of the inventive composition. Accordingly, Examples 12-14, and 16-18 do not support the unexpectedness of the instant formulations.
In regard to Example 15, the instant specification 15 discloses “[t]he first formulation (no poloxamer) included 4% CoQl0; 3% DMPC; and 93% water. The second formulation (with poloxamer) included 4% CoQl0; 3% DMPC; 1.5% Poloxamer Pl88; and 91.5% water.” Example compares the effect of each formulation on cancerous cells. However, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support" (see MPEP 716.02(d) quoting In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)). In the present case the independent claims are not commensurate in scope with example 15. Specifically, example 15 discloses specific concentrations of each component and the independent claims do not. Additionally, the independent claims recited weight ratios outside of the 4:3:1.5 CoQ10:DMPC:p188 demonstrated by example 15.
9) On page 13 of their Remarks, Applicant argues that Betageri does not remedy the deficiencies of the McCook because it does not disclose the formulations of the independent claims.
This argument is not persuasive. Betageri was not relied on for the formulations of the independent claims, rather Betageri is used to support the obviousness of claims 20, 22 and 23.
10) On page 14 of their remarks, Applicant traverses the double patenting rejections.
The instant claims continue to read on the conflicting claims and the rejections stand for the reasons above and of record.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.T.W./Examiner, Art Unit 1612
/WALTER E WEBB/Primary Examiner, Art Unit 1612
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