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 03/11/2026, 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 Rejections and/or objections not reiterated from previous office action are hereby withdrawn.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.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Previous
1) Claims 1, 3-6, 8, 9, 11, 12 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Knoch (WO 2016/146645 A1, publication date 09/22/2016) in view of Hua et al. (Drying Technology, 2003, Vol. 21, No. 8, pp. 1491–1505) and Rahman et al. (WO 90/00389, publication date 01/25/1990).
Regarding instant claims 1, 3-6, 11, and 12, Knoch discloses “cyclosporine formulations for use in the prevention or treatment of pulmonary chronic graft rejection” [abstract]. According to Knoch, “these formulations comprise a therapeutically effective dose of a cyclosporine, an aqueous carrier liquid, a first solubility enhancing substance selected from the group of phospholipids and a second solubility enhancing substance selected from the group of non-ionic surfactants” [p. 8, lines 23-26]. Wherein, “phospholipid is a mixture of natural phospholipids, such as lecithins” (i.e., membrane forming substance according to instant claim 3) [p. 9, line 1] and the non-ionic surfactant may be polysorbate 80 (i.e., solubility enhancing substance according to instant claim 14) [p. 8, lines 3-4]. Knoch also discloses the liposomes formed by the phospholipid (e.g., lecithins) may be in the form of unilamellar liposomes (i.e., liposome with one lipid bilayer; instant claims 3-5) [p. 9, lines 6-8]. Knoch also discloses the composition may be freeze-dried [p. 9, line 17] and that lyoprotective agents such as sucrose (saccharose) and trehalose may be used (i.e., instant claim 11) [p. 9, lines 18-20].
Knoch does not discloses an amount of lyoprotective agent and soy bean lecithin as the membrane forming substance.
Hua studies the effects of cryoprotectants such as sucrose (saccharose) on liposomal formulations with water-soluble and insoluble active agents; ftorafur and vitamin A, respectively [title & abstract]. Hua discloses that “[c]oncentrations [of the cryoprotectants] also have effect on the protective effect of cryoprotectants” [p. 1498, second full para., lines 4-5].
Hua and Knoch do not disclose soy bean lecithin as the membrane forming substance.
Rahman discloses a freeze-dried liposome mixture which is made from the freeze-dried potential liposome mixture [p. 15, claim 10] wherein the cyclosporin may be cyclosporin A [p. 6, line 17], and the amphipathic lipid may be soya bean lecithin (i.e., lecithin containing unsaturated fatty acid residues according to instant claim 12) [p. 6, lines 4-5]. Rahman also discloses the composition may comprise sucrose as a cryoprotectant [p. 8, lines 3-6].
Generally, it is prima facie obvious to select a known material based on its suitability for its intended use. See MPEP 2144.07.
In the present case it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have selected the soya bean lecithin of Rahman as the lecithin desired by Knoch because Rahman discloses it is an appropriate lecithin for liposomal cyclosporine compositions.
Furthermore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have formulated a composition comprising the lyoprotective agent (sucrose and trehalose) within the instantly claimed 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). One of ordinary skill in the art would have been motivated to optimize the composition disclosed by Knoch to find to optimal amount of lyoprotectant agent. One would have had an expectation of success because Hau discloses the concentration of lyoprotective agents, such as sucrose, impacts the protective effects of those agents.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to formulated a lyophilized composition of a liposome forming structure comprising a therapeutically effective amount of cyclosporin A, a membrane forming phospholipid (soy bean lecithin), and a solubility enhancing substance (polysorbate-80) in addition to at least one disaccharide (saccharose). Wherein the disaccharide is present within the instantly claimed amounts. Wherein the phospholipid forms a unilamellar liposome, i.e., a liposome with a single lipid bilayer that defines an inner lumen (i.e., instant claims 4-5). Additionally, because the composition of the prior art is lyophilized, one of ordinary skill in the art would have expected the inner lumen of the liposome forming structures to be at least partially dehydrated (instant claim 6).
Regarding instant claims 8 and 9, Rahman relates to "a freeze-dried potential liposome mixture having amphipathic lipid and cyclosporin" [abstract]. Rahman discloses that sequestration of hydrophobic solutes (i.e., cyclosporin A) occurs within the hydrophobic bilayers [p. 2, lines 23-24]. Rahman also discloses that in the “invention from about 95% to 100% of cyclosporin encapsulated in liposomes prior to freeze-drying is incorporated into liposomes when the freeze-dried mixture is reconstituted” [p. 7, lines 15-17].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the teaching of incorporated cyclosporin into the lipid bilayer by at least 95% of Rahman with the composition taught by Knoch and Hua. One would have been motivated to do so because Rahman teaches that at least 95% is an acceptable range for a liposomal cyclosporin composition. One would have had an expectation of success because the compositions of Rahman are similar to those of Knoch, i.e., lyophilized liposomal cyclosporine compositions. Additionally, 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.
As a result of this combination, a prima facie case of obviousness exists for the instantly claimed range for cyclosporin incorporation because the range of the prior art range (95-100%) overlaps with the instantly claimed range (at least 90%; instant claims 8-9). 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).
Regarding instant claim 30, Knoch discloses providing an aqueous composition: “these formulations comprise a therapeutically effective dose of a cyclosporine, an aqueous carrier liquid, a first solubility enhancing substance selected from the group of phospholipids and a second solubility enhancing substance selected from the group of non-ionic surfactants” [p. 8, lines 23-26]. Knoch also discloses the composition may be freeze-dried [p. 9, line 17].
Given the disclosure of each component individually, it would have been prima facie obvious for a person having ordinary skill in the art at, before the effective filling date of the claimed invention, to have selected and combined known components for their established functions with predictable results by following the teachings of Knoch. MPEP 2143 and 2144.06(I). Therefore it, would have been obvious for one of ordinary skill in the art, before the effective filling date of the claimed invention, to have provided the composition according to Knoch, Hau and Rahman, as set forth above, wherein the composition is obtained by first providing an aqueous dispersion of the composition and then lyophilizing said dispersion.
New by Amendment
2) Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Knoch (WO 2016/146645 A1, publication date 09/22/2016) in view of Hua et al. (Drying Technology, 2003, Vol. 21, No. 8, pp. 1491–1505) Rahman et al. (WO 90/00389, publication date 01/25/1990) as applied to claims 1, 3-6, 8, 9, 11, 12 and 30 above, and further in view of Jangle et al. (Drying Technology, 2013, vol. 31, p. 966-974).
Knoch, Hua and Rahman, which are taught above, differ from the instant claims insofar as they do not disclose disaccharides in the inner lumen of a liposome.
Jangle “evaluates freeze-thaw as a simple approach for screening the most appropriate lyoprotectant” [abstract] and reports that “[t]he internal and external addition of sucrose during formulation has shown significant effects on the retention of particle size and curcumin content during the freeze-thawing and drying studies, respectively” [abstract]. Specifically, “[i]t was observed that internal sucrose with 1X and 2X concentration and external sucrose with 4X and 5X concentration of PC showed the best results with intact vesicle size” [9. 971, col. 1, para. 2, 10-13]. Jangle also discloses that the internal sugar content improved curcumin retention (see Batch A compared to batch C, Table 5 on page 969; provided below).
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It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the internal and external lyoprotective sugar taught by Jangle with the compositions taught by taught by Knoch, Hua and Rahman. One would have been motivated to make this combination to include the lyoprotective sugars inside and outside the liposome because Jangle discloses internal and external concentrations impact drug retention and particle size. One also would have been motivate because Jangle teaches internal concentrations of lyoprotective sugars improve drug retention. One would have had an expectation of success because Jangle discloses these findings with respect to liposomal compositions wherein the encapsulated active is water insoluble. Additionally, 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, before the effective filling date of the claimed invention, to have formulated a lyophilized liposomal cyclosporine A composition, as taught by Knoch, Hua and Rahman, wherein the disaccharide selected from sucrose and trehalose is included in the inner lumen of the liposome.
3) Claims 10, 13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Knoch (WO 2016/146645 A1, publication date 09/22/2016) in view of Hua et al. (Drying Technology, 2003, Vol. 21, No. 8, pp. 1491–1505) and Rahman et al. (WO 90/00389, publication date 01/25/1990) as applied to claims 1, 3-6, 8, 9, 11, 12 and 30 above, and further in view of Keller et al. (US 9,161,963 B2, date of patent 10/20/2015).
Knoch, Hua and Rahman, which are taught above, differ from the instant claims insofar as they do not expressly teach the amounts of phospholipid, cyclosporine A, and the ratio of phospholipid to cyclosporine.
Hua discloses “[t]he concentration for the best protective effects is 5% for glucose, 10% for sucrose, 15% for mannitol, and 10% for trehalose” [p. 1498, second full paragraph 5-7]. One would have understood these percents to refer to the aqueous suspensions because in the methods Hua discloses: “After the samples were sprayed over, the coated pot continued rotating for 20 min, and then the samples were taken out, and placed into a 40mL volumetric flask, distilled water was subsequently added into the volumetric flask, finally the liposomal suspensions containing ftorafur and glucose of 5% concentration were prepared. Samples with other concentrations of glucose, sucrose, mannitol, trehalose in liposomes can be made in a similar way.” [p. 1494, first full paragraph, lines 10-15]. In other words, Hua discloses the weight percent of the sugars with respect to the aqueous suspension.
Keller relates to a liposomal cyclosporin composition [abstract]. Keller discloses a “liquid pharmaceutical composition comprising: (a) a ciclosporin in an amount of up to 5 mg/ml; (b) an aqueous carrier liquid; (c) a first solubility enhancing substance selected from the group of phospholipids; and (d) a second solubility enhancing substance selected from the group of nonionic surfactants, wherein (i) the phospholipid is a lecithin, (ii) the weight ratio of the phospholipid to the nonionic surfactant is between 14:1 and 12:1, (iii) the weight ratio of the phospholipid and the nonionic surfactant to the ciclosporin is between 8:1 and 12:1” [col. 24, claim 1]. Keller also discloses weight ratio of the phospholipid to the nonionic surfactant is between 15:1 to 9:1 [col. 7, lines 20-23].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the amount of lyoprotectant sugars of Hua with the composition of Knoch, Hua and Rahman because Hua discloses those concentrations are the most effective. One would have had an expectation of success because Hua discloses these amounts are suitable for liposomes carrying water insoluble active agents (i.e., vitamin A).
It also would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have combined the weight ratios of Keller with the composition taught by Knoch, Hua and Rahman. On would have been motivated to make this combination because Knoch does not give guidance on this matter and Keller discloses they are suitable weight ratios for liposomal cyclosporin compositions comprising a phospholipid and a solubilizing agent.
Additionally, in combining the elements of Keller with the composition taught by Knoch, Hua and Rahman 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.
One of ordinary skill in the art would have appreciated that this combination encompassed a composition comprising 100mg/ml sucrose or trehalose (i.e., 10% sucrose of trehalose), 5mg/ml cyclosporin, 50 mg/ml phospholipid and surfactant (phospholipid and the nonionic surfactant to the ciclosporin of 10:1). Wherein, of the 50 mg/ml phospholipid and surfactant, 45 mg/ml is phospholipid and 5 mg/ml is surfactant (weight ratio of the phospholipid to the nonionic surfactant of 9:1, when the total combined amount is 50mg/ml). Therefore, the composition taught by Knoch, Hua, Rahman and Keller would have encompassed a lyophilized composition comprising about 64.5% w/w sucrose or trehalose, about 3.2% w/w cyclosporin A, about 29.0% w/w phospholipid (soy bean lecithin) and about 3.2% w/w nonionic surfactant.
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 claimed ranges for the amount of cyclosporin A (2-4% w/w; instant claim 10), the amount of phospholipid (10-30%w/w; instant claim 13) and weight ratio of phospholipid to non-ionic surfactant (15:1 – 9:1; instant claim 15) overlap with the ranges taught by the prior art (about 3% w/w cyclosporin A, 29% phospholipid and 15:1 – 9:1 phospholipid to nonionic surfactant). Accordingly a prima facie case of obviousness exists for each range and claims 10, 13 and 15 are rendered obvious.
Furthermore, while the amounts of disaccharide (sucrose and trehalose) are understood to the obvious over Knoch, Hua and Rahman through routine optimization, as set forth above, those amounts would have also been obvious over Knoch, Hua, Rahman and Keller. 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 this case, the claimed ranges of at least 40% w/w and 50-80% w/w of the lyophilized composition overlap with the range taught by the prior art (i.e., 65.5 % w/w of the lyophilized composition) and so a prima facie case of obviousness exists for the ranges of instant claims 1.
Response to Arguments
1) On pages 11-12 of their Remarks, Applicant argues that “the combination of Knoch and Hua does not disclose, suggest, or even hint at all of the claim limitations, namely” the instantly claimed amounts of disaccharide. Applicant further argues that a skilled artisan would be discouraged from pursuing the claimed compositions because the viscosities resulting from reconstituting the instantly claimed compositions for inhalation may adversely affect the liposomes and may clog the nebulizer or technical parts thereof.
This argument is not persuasive. In the present case, a skilled artisan would have been motivated by Hua to optimize the amount of cryoprotectant sugar because Hua discloses the amount of sugar plays a role in the cryoprotective effect, as discussed above. Additionally, there is nothing directly stated in Knock that would have discredited or discouraged the solution as claimed therefore this argument has not been found persuasive. See MPEP 2123.
2) On pages 12-13 of their Remarks, Applicant argues that saccharose, trehalose or lactose unexpectedly produce liposomes suitable for inhalation as compared to mannitol. Applicant cites the declaration filed 30/11/2026 (paragraphs 10-14) for support.
This argument is not persuasive. The instant specification does not identify that substituting saccaharose, trehalose or lactose in place of mannitol would provide unexpected results. Additionally, these results do not appear to be unexpected because Knoch discloses that sucrose and trehalose are both suitable cryoprotectants for inhalable compositions (Knoch, page 9, lines 18-21). Furthermore, in Example 2 on page 19, Knoch discloses successful nebulization of a reconstituted composition that used sucrose as a cytoprotectant (lyoprotectant). Therefore, a skilled artisan would have expected both sucrose and trehalose to be able to produce liposomes composition suitable for inhalation.
2) On pages 12-13 of their Remarks, Applicant argues the instantly claimed range of 50-80% saccharose, trehalose or lactose unexpectedly produces liposomally solubilized cyclosporine A suitable for inhalation. Applicant cites the declaration filed 30/11/2026 (paragraphs 10-14) for support.
This argument is not persuasive. Overcoming a rejection based on unexpected results requires the combination of three different elements: (i) the results must fairly compare with the prior art, (ii) the results must truly be unexpected and (iii) the claims must be commensurate in scope. MPEP §716.02. The burden rests with Applicant to establish results are unexpected and significant. MPEP §716.02(b). Applicant's showing of allegedly unexpected results does not satisfy any of these requirements.
i. The results are not compared to the closest prior art. The closest prior art appears to be disclosed by Knoch in Example 2 on pages 19-20. Knoch discloses “Sucrose was added as a lyoprotectant to the formulation described in Example 1. Afterwards, the formulation was lyophilized. Immediately before nebulization, the formulation was reconstituted with 2.3 ml 0.25% saline” [p. 19, lines 18-20]. Example 1 disclose a “liposomal cyclosporine liquid formulation for inhalation consisting of the active substance CsA (Ph.Eur.) and the excipients lipoid S100, polysorbate 80, disodium edetate, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate” [p. 18, penultimate para.]. According to Knoch Example 1 delivered “[p]articles smaller than 3.3 μm have a high probability to deposit in the distal part of the lung which is regarded as the optimal drug deposition site for an efficacious lung graft protection” [p. 19, lines 7-9]. Knoch also discloses that Example 2 “results showed no substantial differences in comparison with the results obtained in Example 1” (i.e., suitable for nebulization and inhalation) [p. 20, lines 4-5].
ii. To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). (MPEP 716.02(d)). In the present case Applicant has not provide any examples above the claimed range of disaccharide, i.e., above 80% disaccharide. Additionally, there is a 17% difference from the closest comparative example (34% disaccharide) to the inventive examples (51% disaccharide). As a result, it is not clear if the lower end of the range (50% disaccharide) is critical to the function of the invention.
Accordingly, the Examiner cannot determine if the amount of lyoprotectant is critical to the invention.
Furthermore, it is unclear if the formation of liposomes suitable for inhalation depends on the concentration of lyoprotective disaccharide in the lyophilized composition or the final reconstituted composition. The examples disclosed by applicant vary the amount of lyoprotective disaccharide in both the claimed lyophilized composition and in the reconstituted composition which is not claimed. Accordingly, the Examiner cannot determine if the amount of lyoprotectant in the lyophilized composition is critical to the invention.
iii. 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 examples show support for up to 67% lyoprotectant, not the instantly claimed 80% lyoprotectant. Additionally, results appear to depend on the amount of lyoprotectant resulting in the reconstituted composition, not the instantly claimed lyophilized composition.
3) On page 14 of their Remarks (and paragraph 15 of the declaration), “Applicant respectfully disagrees with the Examiner's conclusion that the skilled person would combine Hua's teachings with Knoch, as Hua has nothing to do with cyclosporine A compositions, but compositions comprising ftorafur or vitamin A.
This argument is not persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, a skilled artisan would have been motivated to combine the prior art references because Hua discusses the efficacy of lyoprotectants such as sucrose and trehalose in liposomal compositions (see abstract) and Knoch desires lyoprotectants such as sucrose and trehalose for a liposomal composition (see p. 9, line 20).
4) On page 14 of their Remarks (and paragraph 15 of the declaration), Applicant argues that a skilled artisan would not have had a reasonable expectation of success in combining Hua and Knoch because “Hua's results also demonstrate that the characteristics of lyophilized liposomal compositions are anything but routine and predictable”.
This argument is not persuasive. The unexpectedness applicant is refereeing to appears to be the result of different active agents, not specific amounts of lyoprotectant disaccharide (see Applicant Remarks at p. 14 first full paragraph):
“Hua discloses retention rates across a wide range of 20-60% for ftorafur depending on the sugar (e.g., Figs. 9-12, Hua) and retention rates across a narrower range of 98-99% for vitamin A (e.g., Table 2, Hua).”
However, Hua is not relied on to show the obviousness of using lyoprotectants with the liposomal cyclosporine A compositions of Knoch. Rather, Hua is relied upon to demonstrate that skilled artisan would have understood that the amount of lyoprotectant impacts the protective effect (see Hua at p. 1498, second full para., lines 4-5). In contrast with the allegedly unpredictable effect of the encapsulated active agent, the effect of lyoprotectant concentration on composition does not appear to be unexpected. See, for example the retention rate increase of Table 2 on page 1502 and of Figure 9 on page 1500 of Hua.
Additionally, a skilled artisan would have already understood that trehalose and sucrose were suitable for the lyophilized compositions of liposomal cyclosporine A because Knoch discloses they are (Knoch at page 9, line 20).
5) On page 14-15 of their Remarks, Applicant argues the instantly claimed amounts of disaccharide result in unexpected dissolution rates. Applicant provides evidence at paragraph 17 and Table 1 of the declaration.
This argument is not persuasive. Overcoming a rejection based on unexpected results requires the combination of three different elements: (i) the results must fairly compare with the prior art, (ii) the results must truly be unexpected and (iii) the claims must be commensurate in scope. MPEP §716.02. The burden rests with Applicant to establish results are unexpected and significant. MPEP §716.02(b). Applicant's showing of allegedly unexpected results does not satisfy any of these requirements.
i. The results are not compared to the closest prior art. The closest prior art appears to be disclosed by Knoch in Example 2 on pages 19-20. Knoch discloses “Sucrose was added as a lyoprotectant to the formulation described in Example 1. Afterwards, the formulation was lyophilized. Immediately before nebulization, the formulation was reconstituted with 2.3 ml 0.25% saline” [p. 19, lines 18-20]. Example 1 disclose a “liposomal cyclosporine liquid formulation for inhalation consisting of the active substance CsA (Ph.Eur.) and the excipients lipoid S100, polysorbate 80, disodium edetate, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate” [p. 18, penultimate para.]. According to Knoch Example 1 delivered “[p]articles smaller than 3.3 μm have a high probability to deposit in the distal part of the lung which is regarded as the optimal drug deposition site for an efficacious lung graft protection” [p. 19, lines 7-9]. Knoch also discloses that Example 2 “results showed no substantial differences in comparison with the results obtained in Example 1” (i.e., suitable for nebulization and inhalation) [p. 20, lines 4-5].
ii. To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). (MPEP 716.02(d)). In the present case the examiner cannot determine the criticality of the claimed range because the amount of lyoprotectant in composition was not disclosed. The only parameter that was changed in the disclosed examples was the concentration of cyclosporine A. Therefore, it is unclear what these comparisons represent and the Examiner cannot determine if the amount of lyoprotectant is critical to the invention.
iii. 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 claims cannot be commensurate in scope with the evidence because the compositions of the examples have not been disclosed.
6) On page 15 of their Remarks, Applicant argues the instant composition demonstrates unexpected stability as evidence by Example 5 of the instant specification which discloses stability at two different concentrations of disaccharide, not one as previously asserted by Examiner.
This argument is not persuasive. Overcoming a rejection based on unexpected results requires the combination of three different elements: (i) the results must fairly compare with the prior art, (ii) the results must truly be unexpected and (iii) the claims must be commensurate in scope. MPEP §716.02. The burden rests with Applicant to establish results are unexpected and significant. MPEP §716.02(b). Applicant's showing of allegedly unexpected results does not satisfy any of these requirements.
i. The results are not compared to the closest prior art. The closest prior art appears to be disclosed by Knoch in Example 2 on pages 19-20. Knoch discloses “Sucrose was added as a lyoprotectant to the formulation described in Example 1. Afterwards, the formulation was lyophilized. Immediately before nebulization, the formulation was reconstituted with 2.3 ml 0.25% saline” [p. 19, lines 18-20]. Example 1 disclose a “liposomal cyclosporine liquid formulation for inhalation consisting of the active substance CsA (Ph.Eur.) and the excipients lipoid S100, polysorbate 80, disodium edetate, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate” [p. 18, penultimate para.]. According to Knoch Example 1 delivered “[p]articles smaller than 3.3 μm have a high probability to deposit in the distal part of the lung which is regarded as the optimal drug deposition site for an efficacious lung graft protection” [p. 19, lines 7-9]. Knoch also discloses that Example 2 “results showed no substantial differences in comparison with the results obtained in Example 1” (i.e., suitable for nebulization and inhalation) [p. 20, lines 4-5].
ii. 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 improved stability of claim does not appears to be, in fact, unexpected in view of the prior art. Keller discloses a aqueous liposomal cyclosporine composition to the instantly discloses composition (see col. 24, claim 1) and according to Keller “The composition can be stored in the fridge (4-80°C.) [understood to be 4-8 deg. C] for at least 12 months, and particularly preferred, for up to 36 months” [col. 14, lines 1-3]. A skilled artisan would have expected the long term stability of such a composition to improve when lyophilized because degradation associated with water (e.g., hydrolysis) would have been reduced.
Furthermore, To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). (MPEP 716.02(d)). In the present case, Example 5 discloses stability results for lyophilized compositions that result in 10% w/v disaccharide and 7.5% w/v disaccharide when reconstituted. The specification does not disclose the exact weight percents of the tested lyophilized compositions. However, the amount of disaccharide in the solid lyophilized composition is understood to be 67%w/w and 61% w/w, respectively, in view of the declaration at paragraph 14. As such, only the stability of compositions according to the instant claims have been discloses. Accordingly, the Examiner cannot determine if the amount of lyoprotectant is critical to the invention.
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 claims are not commensurate in scope because they only discloses results for saccharose in amounts from 61-67% w/w of the lyophilized composition.
7) On page 17 of their Remarks, Applicant argues that “the Examiner picks out certain teachings from each of the cited references to arrive at amounts of each component of the claim lyophilized compositions”.
This argument is not persuasive. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Specifically, a skilled artisan would have been motivated to optimize the amount of lyoprotective disaccharides from Hua’s disclosure that the amount of lyoprotective disaccharides impacts the concomitant lyoprotective effect, as discussed above.
8) Applicant argues that the additional cited references do not remedy the deficiencies of Knoch and Hua.
This argument is not persuasive 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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