Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-3, 5-9 and 11-20 are pending in the present application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/27/2026 has been entered.
Previous Claim Rejections - 35 USC § 103
Claims 1-3, 5-10, 15 and 18 are rejected under 35 U.S.C. 103 as being obvious over WO 2014/041071 and US 10449164 B2 (Gunther et al.; WO ‘071 published March 20, 2014), in view of WO 2018/193093, US 2020/0129543 A1 and US 11273174 B2 (Löscher et al.; WO ‘093 published April 20, 2018); WO 2013/188268 A1 (Böttger et al; published December 19, 2013) and WO 2017/220625 A1, US 2019/0321218 A1 and US 10507132 B2 (Graf et al.; WO ‘625 filed June 21, 2017).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/041071 and US 10449164 B2 (Gunther et al.; WO ‘071 published March 20, 2014), in view of WO 2018/193093, US 2020/0129543 A1 and US 11273174 B2 (Löscher et al.; WO ‘093 published April 20, 2018); WO 2013/188268 A1 (Böttger et al; published December 19, 2013); WO 2017/220625 A1, US 2019/0321218 A1 and US 10507132 B2 (Graf et al.; WO ‘625 filed June 21, 2017); and US 9789080 B2 (Hou et al.).
Applicant traverses the previous rejection on grounds Applicant has discovered a unique problem for the composition of present formula (I), the formation of solid deposits of omega-3 (tidemarks) and loss in concentration of omega-3 fatty acid ester in pharmaceutical compositions, particularly in polypropylene containers. See Applicant’s Remarks dated 02/27/2026, pages 6 -7. Applicant alleges the inclusion of liquid paraffin or light liquid paraffin is enough to prevent this formation of tidemarks and loss of omega-3 fatty acid ester. See page 7, first two lines and last two lines of second paragraph. Applicant alleges Löscher and Böttger further do not contemplate stability with regards to omega-3 fatty acid ester deposition, disclose the problem of tidemark formation, or the solution of less than 1 wt.% light liquid paraffin to prevent the deposition of omega-3 fatty acid esters. Applicant alleges Gunther discloses stability as it relates to stability of the active compounds in terms of oxidation and degradation and further does not contemplate the presence of tidemark formation. Applicant argues the prior art does not teach or suggest this problem of tidemark formation especially in polypropylene containers. See pages 8-9 of Applicant’s Remarks dated 02/27/2026. Applicant has amended claim 1 to require “up to 0.1 wt% of antioxidant”. Applicant further alleges the unexpected results of the present disclosure are now commensurate in scope with the present claims and the prior art does not teach a specific composition comprising antioxidants, rendering the alleged discovered properties non-inherent. Applicant argues only with improper hindsight the person of skill would arrive at the present claimed composition as the prior art does not provide a motivation to add antioxidant to the composition. See page 10.
The Examiner has considered the amendment and traversal fully but must disagree for the following reasons.
Regarding the formation of solid deposits of omega-3 fatty acid ester (tidemarks) and loss in concentration of omega-3 fatty acid ester in pharmaceutical compositions, particularly in polypropylene containers, these limitations are interpreted as an intended results for the composition of instant claim 1 and thus not given patentable weight. A recitation of the intended result of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. Regarding an intended use limitation, MPEP 2111.02(II) notes: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”. In this situation, the limitation does not affect the structure of the composition of instant claim 1.
Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (Claims were directed to grooved carbon disc brakes wherein the grooves were provided to vent steam or vapor during a braking action. A prior art reference taught noncarbon disc brakes which were grooved for the purpose of cooling the faces of the braking members and eliminating dust. The court held the prior art references when combined would overcome the problems of dust and overheating solved by the prior art and would inherently overcome the steam or vapor cause of the problem relied upon for patentability by applicants. Granting a patent on the discovery of an unknown but inherent function (here venting steam or vapor) "would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art." 596 F.2d at 1022, 201 USPQ at 661.); In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991). "[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. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In the present situation, the discovery of unrecognized or unknown properties of the composition of instant claim 1 which are inherently present does not render the instant invention nonobvious nor patentable.
It is noted that the features upon which Applicant relies (e.g., the formation of solid deposits of omega-3 fatty acid ester (tidemarks)) are not recited in the rejected claims and, therefore, these features do not carry any weight in terms of an obviousness analysis. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006). See MPEP 2144, Section IV. The court held "it is not necessary in order to establish a prima facie case of obviousness...that there be a suggestion or expectation from the prior art that the claimed [invention] will have the same or a similar utility as one newly discovered by applicant," and concluded that here a prima facie case was established because "[t]he art provided the motivation to make the claimed compositions in the expectation that they would have similar properties." In re Dillon, 919 F.2d at 693, 16 USPQ2d at 1901 (emphasis in original).
A person having ordinary skill in the art that prepares the ophthalmic composition of Gunther would have been motivated to apply carriers/excipients that have been applied in analogous solvent systems and/or for analogous conditions, as disclosed by Löscher, Böttger and Graf. It appears that given the constituents would result in the instant properties, the prior art compositions could anticipate the instant claims where "products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical composition, the properties applicant discloses and/or claims are necessarily present. Id. See MPEP 2112.01(II). The reduction in tidemark formation, claimed stability of the omega-3 fatty acid ester as well as stability of the ophthalmic pharmaceutical composition as required by claim 1 would be present in the composition disclosed by Gunther and further modified by Löscher, Böttger and Graf. One of ordinary skill does not need the same motivation to include liquid paraffin, light liquid paraffin or antioxidants as an excipient to the pharmaceutical composition to achieve the intended results of reduction of tidemark formation.
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998). See also MPEP 2123.
The Examiner agrees the results provided are now commensurate in scope with the claims; however, upon reconsideration of the prior art which discloses ophthalmic pharmaceutical compositions which are stable (less than 1% degradation of active agent) during storage of more than 18 months, the result cannot be considered unexpected in the field of ophthalmic pharmaceutical compositions. Further, as noted in Applicant’s remarks and the present specification, liquid paraffin is disclosed as the solution to the problem of tidemark formation, not only light liquid paraffin. Gunther discloses liquid paraffin as a useful lipid excipient in the ophthalmic pharmaceutical composition and both Loscher and Böttger disclose ophthalmic pharmaceutical compositions comprising light liquid paraffin.
Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). The prior art need not disclose a single embodiment where antioxidants are included in the pharmaceutical composition. As the prior art composition are directed to an analogous field, ophthalmic compositions, one of ordinary skill in the art would have motivation to combine the teachings to provide a storage-stable composition. Both Gunther and Graf disclose the inclusion of antioxidant as excipient in the ophthalmic pharmaceutical composition. There would be a reasonable expectation of success given the teachings of mass percentages that overlap with the required amounts in the present claims and the various discussions of composition stability for months and even over one year.
In response to applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). See MPEP 2145(X), Subsection A.
"A factfinder should be aware, of course, of the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning. Applicants may also argue that the combination of two or more references is "hindsight" because "express" motivation to combine the references is lacking. However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness." Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See KSR, 550 U.S. at 402, 82 USPQ2d at 1389
Gunther teaches a stable ophthalmic composition comprising, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane F6H8, also comprising excipients such as liquid paraffin and antioxidants for the treatment of dry eye. Löscher and Böttger disclose ophthalmic compositions comprising both light liquid paraffin and F6H8 as vehicles for the treatment of similar ocular disease. Graf teaches liquid ophthalmic compositions comprising F6H8 and further useful antioxidants BHA and BHT. One of ordinary skill in the art would have been motivated to combine these teachings to arrive at a stable ophthalmic composition of the present invention. A person having ordinary skill in the art in ophthalmic compositions within the general disclosure of Gunther would have been motivated to apply carriers/excipients that have been applied in analogous solvent systems and/or for analogous conditions, as disclosed by Löscher.
Gunther teaches where the composition retains more than 75% wt. of omega-3 ethyl ester after storage for 3 months at 40 °C and a relative humidity of 75% (see present claim 10). See Table 3 of Gunther. Löscher also discloses the composition of the present invention, is stable without protection from light; preferably the composition is stable for at least 30 days; more preferably, stable for at least 90 days; or even more preferably, stable for at least 180 days at room temperature without protection from light. See page 20, first and second paragraphs. Böttger also teaches the pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not degrade significantly (< 1 %) during storage. See page 10, second to last paragraph.
There would be a reasonable expectation of success based on the exemplary compositions disclosed in the prior art as well as the stability disclosed for the ophthalmic pharmaceutical composition.
Therefore, the previous rejection is maintained in an amended form necessitated by Applicant’s amendment.
Claim Objections
Claim 20 is objected to because of the following informalities:
In claim 20, last line, “eicosapentaenoic” should read, “eicosapentaenoic acid ethyl ester”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 15 and 18 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.
Claim 15 recites the limitation "the storage means" in line 3 of claim 15. There is insufficient antecedent basis for this limitation in the claim as claim recites “A kit comprising a container”. Applicant can amend claim 15 to recite “wherein the container is a polypropylene container” to overcome this rejection.
Claim 18 recites the limitation “the kit according to claim 14”, in line 1 of present claim 18. Claim 14 is directed to a method of claim 12, wherein the condition is selected from a Markush group of conditions of the eye, which is withdrawn from examination. There is insufficient antecedent basis for the limitation of “the kit according to claim 14” in instant claim 15.
Claims 1-3, 5-9, 15 and 18-20 are rejected under 35 U.S.C. 103 as being obvious over WO 2014/041071 and US 10449164 B2 (Gunther et al.; WO ‘071 published March 20, 2014), in view of WO 2018/193093, US 2020/0129543 A1 and US 11273174 B2 (Löscher et al.; WO ‘093 published April 20, 2018); WO 2013/188268 A1 (Böttger et al; published December 19, 2013) and WO 2017/220625 A1, US 2019/0321218 A1 and US 10507132 B2 (Graf et al.; WO ‘625 filed June 21, 2017).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Gunther teaches stable liquid ophthalmic composition comprising omega-3 fatty acid esters, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane of formula F(CF2)6(CH2)8H at concentrations of 1.0 wt. % and 5.0 wt.% (see present claims 3 and 20). See pages 7, 9-10 of Gunther and Example 1 on pages 21-23.
Gunther discloses the medicament may be used for the treatment of a condition or disease of an eye or ophthalmic tissue such as inflammatory conditions of the ophthalmic tissue or keratoconjunctivitis sicca (dry eye). See page 18, first paragraph to page 19, first paragraph.
Gunther also teaches excipients of the ophthalmic composition are preferably selected from lipids, oils, lubricants, lipophilic vitamins, viscosity agents, antioxidants, surfactants and mixtures of two or more thereof. Examples of potentially useful lipids and oily excipients and which may be included in the compositions of the invention include triglyceride oils (e.g. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), mineral oil (e.g. petrolatum and liquid paraffin). See page 20, paragraphs 1-3.
Gunther also teaches a pharmaceutical kit comprising the composition as described above and a container holding the composition. Gunther discloses where preferably, the container which contains the composition has a dispensing means such as a dropping device adapted for topically administering the composition to the eye of a patient (see present claim 15). See page 21, lines 15-20.
Gunther teaches where the composition retains more than 75% wt. of omega-3 ethyl ester after storage for 3 months at 40 °C and a relative humidity of 75% (see present claim 19). See Table 3 of Gunther.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Gunther does not teach a stable liquid ophthalmic composition comprising up to 1 wt% light liquid paraffin or up to 0.1 wt% of antioxidant.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Löscher teaches a composition comprising molecular iodine and a vehicle comprising a semifluorinated alkane, for use as a medicament preferably for the treatment or prevention of a disease or condition of the eye or an ophthalmic tissue, including ocular dryness. See page 2, paragraph 3 and page 23, second paragraph. The particularly preferred semifluorinated alkane, F6H8, comprised by the liquid vehicle of the composition of the present invention also known as l-perfluorohexyl-octane. See page 7, first paragraph.
With regards to the amounts of the vehicle or excipients present, Löscher also teaches the vehicle may consist of at least 70% (w/w), 75 % (w/w), 85 % (w/w), 90 % (w/w), 95 % (w/w), 98% or at least 99 % (w/w) of a semifluorinated alkane or a mixture of semifluorinated alkanes, with respect to the total weight of the vehicle, and a co- solvent or excipient preferably a non-polar co-solvent or excipient (see present claim 7). See page 13, second and third paragraphs. Löscher discloses in one embodiment; the amount of excipient featured in a composition according to the invention may be in an amount of no more than 30% (w/w), 25% (w/w), 15% (w/w) or 10 % (w/w), or 5 % (w/w), 2% (w/w), or about 1.0 % (w/w) in respect to the total weight amount of the vehicle. See page 16, second to last paragraph.
Löscher also teaches ophthalmic compositions comprising both semiflourinated alkane 1-perfluorohexyl-octane (F6H8) and light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil). See the fifth and sixth entries from the bottom of Table 1 on page 41. The F6H8 and light liquid paraffin are present in the ophthalmic composition in a ratio of 6.67:1 (w/w) (light liquid paraffin is present in a range of 9.1-12.9 %(w/w)).
Löscher also discloses the composition of the present invention, is stable without protection from light; preferably the composition is stable for at least 30 days; more preferably, stable for at least 90 days; or even more preferably, stable for at least 180 days at room temperature without protection from light. See page 20, first and second paragraphs.
Böttger teaches a topical ophthalmological pharmaceutical composition comprising pazopanib, a hydrate, solvate or pharmaceutically acceptable salt of pazopanib or a polymorph thereof as active agent and at least one non-aqueous pharmaceutically acceptable vehicle and optionally at least one pharmaceutically acceptable excipient wherein the composition is a non-aqueous solution comprising the active agent dissolved in the non-aqueous applicable pharmaceutically acceptable vehicle. See page 4, second and third paragraph.
Böttger teaches most preferably hydrophobic vehicles are used which include but are not limited to liquid paraffin or light liquid paraffin or a mixture thereof. See page 7, second paragraph.
Böttger discloses the suspension according to the present invention comprising a lipophilic vehicle like liquid paraffin or light liquid paraffin provides by topical administration a sufficient amount of the active agent to the back of the eye which is effective for treating a posterior eye disease. See page 13, second to last paragraph.
Böttger teaches an exemplary ophthalmological suspension comprising pazopanib hydrochloride in liquid paraffin (20 mg/ml). See Examples 1 and 2 on pages 16-19.
Böttger also teaches the pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not degrade significantly (< 1 %) during storage. See page 10, second to last paragraph.
Graf teaches a method for dropwise topical administration of a liquid composition, where the liquid composition is preferably a liquid solution that may be applied to the human or animal body and that, may optionally contain one or more active pharmaceutical ingredient (API) as defined above or further compounds like excipients, such as organic solvents, lipids, oils, lipophilic vitamins, lubricants, viscosity agents, acids, bases, antioxidants, stabilizers, synergists, coloring agents, thickening agents, - and if required in a particular cases - a preservative or a surfactant and mixtures thereof. See page 6, third paragraph to the second to last paragraph. Graf discloses the liquid ophthalmic composition comprises a liquid semifluorinated alkane or a mixture of two or more different semifluorinated alkanes, including F6H8. See page 13, second to last paragraph to page 16, first paragraph.
Graf discloses useful antioxidants to include in the liquid ophthalmic composition comprise butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) or acetylcysteine (see present claim 9).
Gunther teaches stable liquid ophthalmic composition comprising omega-3 fatty acid esters, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane of formula F(CF2)6(CH2)8H at concentrations of 1.0 wt% and 5.0 wt%. Gunther also teaches excipients of the ophthalmic composition include liquid paraffin. Löscher teaches a composition comprising molecular iodine and a vehicle comprising F6H8, for use as a medicament preferably for the treatment or prevention of a disease or condition of the eye or an ophthalmic tissue, including ocular dryness. Löscher also teaches ophthalmic compositions comprising both semiflourinated alkane 1-perfluorohexyl-octane (F6H8) and light liquid paraffin. Böttger teaches a topical ophthalmological pharmaceutical composition comprising pazopanib, a hydrate, solvate or pharmaceutically acceptable salt of pazopanib or a polymorph thereof as active agent and at least one non-aqueous pharmaceutically acceptable vehicle and optionally at least one pharmaceutically acceptable excipient wherein the composition is a non-aqueous solution comprising the active agent dissolved in the non-aqueous applicable pharmaceutically acceptable vehicle. Böttger teaches the ophthalmological composition comprising a lipophilic vehicle like liquid paraffin or light liquid paraffin provides by topical administration a sufficient amount of the active agent to the back of the eye which is effective for treating a posterior eye disease.
"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05, Section II, subsection A.
With regards to the specific wt.% amounts of the DHA-EE, liquid paraffin and semifluorinated alkane required of present claims 1-2 and claims 6-9, Gunther discloses ophthalmic composition comprising DHA-EE at a concentration of 1 and 5 wt.% in F6H8 semifluorinated alkane vehicle. Löscher provides guidance on compositions comprising both F6H8 vehicle and light liquid paraffin co-solvent or excipient, where the vehicle may consist of at least 70% (w/w), 75 % (w/w), 85 % (w/w), 90 % (w/w), 95 % (w/w), 98% or at least 99 % (w/w) of a semifluorinated alkane and the amount of excipient featured in a composition according to the invention may be in an amount of no more than 30% (w/w), 25% (w/w), 15% (w/w) or 10 % (w/w), or 5 % (w/w), 2% (w/w), or about 1.0 % (w/w) in respect to the total weight amount of the vehicle. Graf teaches liquid ophthalmic compositions comprising F6H8 and further useful antioxidants BHA and BHT. It would have been obvious to one of ordinary skill in the art to adjust the relative concentrations of the components of the ophthalmic composition disclosed by the combination of Gunther, Löscher, Böttger and Graf.
Gunther teaches a stable ophthalmic composition comprising, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane F6H8, also comprising excipients such as liquid paraffin and antioxidants for the treatment of dry eye. Löscher and Böttger disclose ophthalmic compositions comprising both light liquid paraffin and F6H8 as vehicles for the treatment of similar ocular disease. Graf teaches liquid ophthalmic compositions comprising F6H8 and further useful antioxidants BHA and BHT. One of ordinary skill in the art would have been motivated to combine these teachings to arrive at a stable ophthalmic composition of the present invention. A person having ordinary skill in the art in ophthalmic compositions within the general disclosure of Gunther would have been motivated to apply carriers/excipients that have been applied in analogous solvent systems and/or for analogous conditions, as disclosed by Löscher.
Gunther teaches where the composition retains more than 75% wt. of omega-3 ethyl ester after storage for 3 months at 40 °C and a relative humidity of 75% (see present claim 19). See Table 3 of Gunther. Löscher also discloses the composition of the present invention, is stable without protection from light; preferably the composition is stable for at least 30 days; more preferably, stable for at least 90 days; or even more preferably, stable for at least 180 days at room temperature without protection from light. See page 20, first and second paragraphs. Böttger also teaches the pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not degrade significantly (< 1 %) during storage. See page 10, second to last paragraph.
There would be a reasonable expectation of success based on the exemplary compositions disclosed in the prior art as well as the stability disclosed for the ophthalmic pharmaceutical composition.
Regarding present claim 18, the claim is interpreted as a product-by-process claim (the claim is directed to an ophthalmic pharmaceutical composition, where the omega-3 fatty acid esters of the composition are prevented from absorbing to the polypropylene material when the composition is packaged into a polypropylene container), and the patentability is determined based on the ophthalmic pharmaceutical composition product alone. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113 (I). As the combination of Gunther, Löscher, Böttger and Graf disclose the liquid ophthalmic pharmaceutical composition of present claim 1, the subject matter of present claim 18 is also disclosed.
Regarding the limitations of where the composition is a “stable” liquid ophthalmic pharmaceutical composition and “wherein the composition retains more than 75 wt% for 3 months of omega-3 ethyl ester upon storage at 40 °C at a relative humidity of 75%, when the composition is packaged into a polypropylene container”, MPEP 2111.02(II) notes:
“If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”.
In this situation, the limitation does not affect the structure of the pharmaceutical composition. A person having ordinary skill in the art that prepares the ophthalmic composition of Gunther would have been motivated to apply carriers/excipients that have been applied in analogous solvent systems and/or for analogous conditions, as disclosed by Löscher and Böttger. It appears that given the constituents would result in the instant properties, the prior art compositions could anticipate the instant claims where "products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical composition, the properties applicant discloses and/or claims are necessarily present. Id. See MPEP 2112.01(II). The claimed stability of the omega-3 fatty acid and generally of the ophthalmic pharmaceutical composition as required by claim 19 would be present in the composition disclosed by Gunther and further modified by Löscher, Böttger and Graf. It is noted the container or packaging employed for carrying a particular composition does not have relevance in the particular structure or agents of said composition.
Therefore, the present claims are prima facie obvious.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/041071 and US 10449164 B2 (Gunther et al.; WO ‘071 published March 20, 2014), in view of WO 2018/193093, US 2020/0129543 A1 and US 11273174 B2 (Löscher et al.; WO ‘093 published April 20, 2018); WO 2013/188268 A1 (Böttger et al; published December 19, 2013); WO 2017/220625 A1, US 2019/0321218 A1 and US 10507132 B2 (Graf et al.; WO ‘625 filed June 21, 2017); and US 9789080 B2 (Hou et al.).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Gunther teaches stable liquid ophthalmic composition comprising omega-3 fatty acid esters, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane of formula F(CF2)6(CH2)8H at concentrations of 1.0 wt. % and 5.0 wt. % (see present claim 3). See pages 7, 9-10 of Gunther and Example 1 on pages 21-23.
Gunther discloses the medicament may be used for the treatment of a condition or disease of an eye or ophthalmic tissue such as inflammatory conditions of the ophthalmic tissue or keratoconjunctivitis sicca (dry eye). See page 18, first paragraph to page 19, first paragraph.
Gunther also teaches excipients of the ophthalmic composition are preferably selected from lipids, oils, lubricants, lipophilic vitamins, viscosity agents, antioxidants, surfactants and mixtures of two or more thereof. Examples of potentially useful lipids and oily excipients and which may be included in the compositions of the invention include triglyceride oils (e.g. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), mineral oil (e.g. petrolatum and liquid paraffin). See page 20, paragraphs 1-3.
Gunther also teaches a pharmaceutical kit comprising the composition as described above and a container holding the composition. Gunther discloses where preferably, the container which contains the composition has a dispensing means such as a dropping device adapted for topically administering the composition to the eye of a patient (see present claim 15). See page 21, lines 15-20.
Gunther teaches where the composition retains more than 75% wt. of omega-3 ethyl ester after storage for 3 months at 40 °C and a relative humidity of 75% (see present claim 10). See Table 3 of Gunther.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
Gunther does not teach a stable liquid ophthalmic composition comprising light liquid paraffin, wherein the oxygen content of the composition is below 0.90 µg/ml.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
Löscher teaches a composition comprising molecular iodine and a vehicle comprising a semifluorinated alkane, for use as a medicament preferably for the treatment or prevention of a disease or condition of the eye or an ophthalmic tissue, including ocular dryness. See page 2, paragraph 3 and page 23, second paragraph. The particularly preferred semifluorinated alkane, F6H8, comprised by the liquid vehicle of the composition of the present invention also known as l-perfluorohexyl-octane. See page 7, first paragraph.
With regards to the amounts of the vehicle or excipients present, Löscher also teaches the vehicle may consist of at least 70% (w/w), 75 % (w/w), 85 % (w/w), 90 % (w/w), 95 % (w/w), 98% or at least 99 % (w/w) of a semifluorinated alkane or a mixture of semifluorinated alkanes, with respect to the total weight of the vehicle, and a co- solvent or excipient preferably a non-polar co-solvent or excipient (see present claim 7). See page 13, second and third paragraphs. Löscher discloses in one embodiment; the amount of excipient featured in a composition according to the invention may be in an amount of no more than 30% (w/w), 25% (w/w), 15% (w/w) or 10 % (w/w), or 5 % (w/w), 2% (w/w), or about 1.0 % (w/w) in respect to the total weight amount of the vehicle. See page 16, second to last paragraph.
Löscher also teaches ophthalmic compositions comprising both semiflourinated alkane 1-perfluorohexyl-octane (F6H8) and light liquid paraffin (low viscosity paraffin, Paraffinum perliquidum, light mineral oil). See the fifth and sixth entries from the bottom of Table 1 on page 41. The F6H8 and light liquid paraffin are present in the ophthalmic composition in a ratio of 6.67:1 (w/w).
Löscher also discloses the composition of the present invention, is stable without protection from light; preferably the composition is stable for at least 30 days; more preferably, stable for at least 90 days; or even more preferably, stable for at least 180 days at room temperature without protection from light. See page 20, first and second paragraphs.
Böttger teaches a topical ophthalmological pharmaceutical composition comprising pazopanib, a hydrate, solvate or pharmaceutically acceptable salt of pazopanib or a polymorph thereof as active agent and at least one non-aqueous pharmaceutically acceptable vehicle and optionally at least one pharmaceutically acceptable excipient wherein the composition is a non-aqueous solution comprising the active agent dissolved in the non-aqueous applicable pharmaceutically acceptable vehicle. See page 4, second and third paragraph.
Böttger teaches most preferably hydrophobic vehicles are used which include but are not limited to liquid paraffin or light liquid paraffin or a mixture thereof. See page 7, second paragraph.
Böttger discloses the suspension according to the present invention comprising a lipophilic vehicle like liquid paraffin or light liquid paraffin provides by topical administration a sufficient amount of the active agent to the back of the eye which is effective for treating a posterior eye disease. See page 13, second to last paragraph.
Böttger teaches an exemplary ophthalmological suspension comprising pazopanib hydrochloride in liquid paraffin (20 mg/ml). See Examples 1 and 2 on pages 16-19.
Böttger also teaches the pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not degrade significantly (< 1 %) during storage. See page 10, second to last paragraph.
Hou teaches an ophthalmic formulation including mycophenolic acid or salt thereof as an active ingredient can be prepared by reducing the level of oxygen dissolved in the medium or formulation to less than 3.0 ppm, e.g., less than 2.0 ppm and preferably less than 1.0 ppm such as no more than 0.5 ppm. See col. 4, paragraph 3.
Hou also discloses the dissolved oxygen level of the formulation can be determined with VWR Symphony, model SP70D, meter or an equivalent meter. Preferably the oxygen meter should have a relative accuracy of about 0.2 mg/L. The measurement is taken at room temperature (i.e., 20° C.) under one atmosphere and physiological pH.
Hou further discloses a method of treating a subject having Sjogren’s syndrome, rheumatoid arthritis, or lupus, for example, or treating dry eye with an ophthalmic formulation including mycophenolic acid or salt thereof and a deoxygenated aqueous medium. See col. 2, paragraph 3.
Hou discloses that ophthalmic formulations including mycophenolic acid or salt thereof as an active ingredient in an aqueous medium with a reduced level of dissolved oxygen relative to saturation level were more stable than formulations with aqueous media having saturated levels of dissolved oxygen. The improved stability allows for the manufacture of ophthalmic formulations containing mycophenolic acid or salt thereof with a significantly improved shelf-life, e.g., formulations having a shelf-life of over 12 months.
"[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05, Section II, subsection A.
With regards to the specific wt.% amounts of the DHA-EE, liquid paraffin and semifluorinated alkane required of present claims 1-2 and claims 6-9, Gunther discloses ophthalmic composition comprising DHA-EE at a concentration of 1 and 5 wt% in F6H8 semifluorinated alkane vehicle. Löscher provides guidance on compositions comprising both F6H8 vehicle and light liquid paraffin co-solvent or excipient, where the vehicle may consist of at least 70% (w/w), 75% (w/w), 85 % (w/w), 90 % (w/w), 95 % (w/w), 98% or at least 99 % (w/w) of a semifluorinated alkane and the amount of excipient featured in a composition according to the invention may be in an amount of no more than 30% (w/w), 25% (w/w), 15% (w/w) or 10 % (w/w), or 5 % (w/w), 2% (w/w), or about 1.0 % (w/w) in respect to the total weight amount of the vehicle. Graf teaches liquid ophthalmic compositions comprising F6H8 and further useful antioxidants BHA and BHT. It would have been obvious to one of ordinary skill in the art to adjust the relative concentrations of the components of the ophthalmic composition disclosed by the prior art.
Gunther teaches stable liquid ophthalmic composition comprising omega-3 fatty acid esters, eicosapentaenoic acid ethyl ester (EPA-EE) and docosahexenoic acid ethyl ester (DHA-EE), prepared in a liquid vehicle comprising a semifluorinated alkane of formula F(CF2)6(CH2)8H at concentrations of 1.0 wt. % and 5.0 wt. %. Gunther also teaches excipients of the ophthalmic composition include liquid paraffin. Löscher teaches a composition comprising molecular iodine and a vehicle comprising F6H8, for use as a medicament preferably for the treatment or prevention of a disease or condition of the eye or an ophthalmic tissue, including ocular dryness. Löscher also teaches ophthalmic compositions comprising both semiflourinated alkane 1-perfluorohexyl-octane (F6H8) and light liquid paraffin. Böttger teaches the ophthalmological composition comprising a lipophilic vehicle like liquid paraffin or light liquid paraffin provides by topical administration a sufficient amount of the active agent to the back of the eye which is effective for treating a posterior eye disease. Graf teaches liquid ophthalmic compositions comprising F6H8 and further useful antioxidants BHA and BHT. Hou teaches an ophthalmic formulation including mycophenolic acid or salt thereof as an active ingredient can be prepared by reducing the level of oxygen dissolved in the medium or formulation to less than 3.0 ppm, e.g., less than 2.0 ppm and preferably less than 1.0 ppm such as no more than 0.5 ppm. See col. 4, paragraph 3.
One of ordinary skill in the art would have been motivated to combine these teachings to arrive at a stable ophthalmic composition of the present invention. A person having ordinary skill in the art in ophthalmic compositions within the general disclosure of Gunther would have been motivated to apply carriers/excipients that have been applied in analogous solvent systems and/or for analogous conditions, as disclosed by Löscher.
Gunther teaches where the composition retains more than 75% wt. of omega-3 ethyl ester after storage for 3 months at 40 °C and a relative humidity of 75% (see present claim 10). See Table 3 of Gunther. Löscher also discloses the composition of the present invention, is stable without protection from light; preferably the composition is stable for at least 30 days; more preferably, stable for at least 90 days; or even more preferably, stable for at least 180 days at room temperature without protection from light. See page 20, first and second paragraphs. Böttger also teaches the pharmaceutical composition according to the invention is chemically stable for more than 18 months, preferably more than 24 months. Chemically stable according the present invention means that the active agent does not degrade significantly (< 1 %) during storage. See page 10, second to last paragraph. There would be a reasonable expectation of success based on the exemplary compositions disclosed in the prior art as well as the stability disclosed for the ophthalmic pharmaceutical composition.
Furthermore, one of ordinary skill in the art would have been motivated by the disclosure of Hou to produce a composition that essentially free of oxygen to improve stability of the composition. As Hou discloses an ophthalmic composition, a method of determining the level of dissolved oxygen within the composition and similarly a method for treating dry eye comprising administration of the disclosed composition, there would be a reasonable expectation of success.
Therefore, the claims are prima facie obvious.
Conclusion
Claims 1-3, 5-9 and 11-20 are pending in the present application.
Claims 12-14 and 16-17 are withdrawn.
Claims 1-3, 5-9, 11, 15 and 18-20 are rejected.
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/QUINCY A. MCKOY/
Patent Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626