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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/04/2026 has been entered.
Applicants’ arguments, filed 09/04/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 Interpretation
Claim 11 recites “saccharose (sucrose)” which are interpreted as two names for the same substance.
Instant claim 30 recites “obtainable by a process” which is interpreted to mean capable of being obtained by the claimed process.
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.
1) Claims 1, 3-6, 11, 12, and 30-33 are rejected under 35 U.S.C. 103 as being unpatentable over Knoch (WO 2016/146645 A1, publication date 09/22/2016), as evidenced by Lipoid (Unsaturated Phospholipids, Lipoid, retrieved 9/29/26, https://lipoid.com/en/products/natural-phospholipids/unsaturated-phospholipids/).
Knoch discloses “cyclosporine formulations for use in the prevention or treatment of pulmonary chronic graft rejection” [abstract]. In Example 1 Knoch discloses a “liposomal cyclosporine liquid formulation for inhalation consisting of the active substance CsA (Ph.Eur.) [cyclosporine A] and the excipients lipoid S100, polysorbate 80, disodium edetate” (i.e., a polysorbate solubility enhancer and a liquid formulation comprising one more excipient as per instant claim 30) [p. 18, lines 7-8]. Later in Example 2, Knoch discloses “[s]ucrose was added as a lyoprotectant to the formulation described in Example 1” [p. 19, lines 18] (i.e., saccharose; instant claims 1, 11 and 30). “Afterwards, the formulation was lyophilized” (i.e., lyophilizing liquid as per the method of instant claim 30) [p. 19, lines 18-20].
Lipoid S100 is an unsaturated phospholipid from soybean lecithin with >/= 94% phosphatidylcholine content (i.e., a lecithin containing unsaturated fatty acid residue; instant claims 1, 12), as evidenced by Lipoid at pages 1 and 2.
Knoch does not anticipate the instant claims because it does not disclose a specific amount of sucrose in the lyophilized composition.
However, 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 the lyophilized composition of Knoch’s Example 2 to comprising sucrose 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 the optimum workable ranges of sucrose as the lyoprotectant. One would have had an expectation of success because Knoch discloses sucrose is a lyoprotectant.
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 composition comprising a liposome structure of cyclosporine A, a soybean lecithin containing unsaturated fatty acid residues (lipoid S100) and a polysorbate solubility enhancing substance, and also comprising saccharose (sucrose) within the instantly claimed amounts (instant claims 1, 11, 12 and 31). Wherein the lyophilized composition is obtained by lyophilizing a liquid formulation and may comprise additional excipients (disodium edetate), as per instant claim 30. Additionally, since the prior art composition contains substantially the same components, i.e., the same lyophilized liposomal cyclosporine A and sucrose, in the same relative proportions as instantly claimed, it would be expected to inherently possess the same chemical and physical properties, such as being obtainable by the methods of instant claim 30, and having the same dissolution and storage stability properties (instant claims 32 and 33). Please refer to MPEP2112.01 (II).
Knoch discloses the liposomes formed by the phospholipid (e.g., lecithins) may be in the form of unilamellar liposomes [p. 9, lines 6-8], as per instant claim 4.
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 unilamellar liposomes in Knoch with the exemplary liposomal compositions of Knoch. One would have been motivated, and had an expectation of success in making this combination because Knoch discloses unilamellar liposomes are suitable for the compositions disclosed therein. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, 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 the composition as discussed above, wherein the liposomes are at least partly present in unilamellar form (instant claim 4). Additionally, since the prior art composition contains substantially the same components, i.e., unilamellar lyophilized liposomal cyclosporine and sucrose, in the same relative proportions as instantly claimed, it would be expected to inherently possess the same chemical and physical properties, such as having a lipid bilayer (i.e., unilamellar liposome; instant claim 3) and an inner lumen (instant claim 5) that is partially dehydrated (i.e., lyophilized; instant claim 6). Please refer to MPEP2112.01 (II).
2) Claims 1, 3-8, 10-13, 15, 30-33 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 Wong et al. (US 2006/0110441 A1, publication date 05/25/2006) and Keller et al. (US 9,161,963 B2, date of patent 10/20/2015), as evidenced by Lipoid (Unsaturated Phospholipids, Lipoid, retrieved 9/29/26, https://lipoid.com/en/products/natural-phospholipids/unsaturated-phospholipids/).
While the independent claims are understood to be obvious over Knoch alone, purely arguendo the claims would have also been obvious over Knoch in view of Wong and Keller. Regarding instant claims 1, 3-6, 11, 12, 32 and 33, 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” [p. 9, line 1] and the non-ionic surfactant may be polysorbate 80 (i.e., solubility enhancing agent according to claim 1) [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]. In Example 1 Knoch discloses a “liposomal cyclosporine liquid formulation for inhalation consisting of the active substance CsA (Ph.Eur.) [cyclosporine A] and the excipients lipoid S100, [and] polysorbate 80” [p. 18, lines 7-8]. Later in Example 2, Knoch discloses “[s]ucrose was added as a lyoprotectant to the formulation described in Example 1” [p. 19, lines 18] (i.e., saccharose; instant claims 1, 11 and 30). “Afterwards, the formulation was lyophilized” (i.e., lyophilizing liquid as per instant claim 30) [p. 19, lines 18-20]. Finally, Knoch discloses “[t]he formulation preferably contains cyclosporine at a concentration between about 0.5 and 10 mg/ml” [p. 11, lines 38-39].
Lipoid S100 is an unsaturated phospholipid from soybean lecithin with >/= 94% phosphatidylcholine content (i.e., a lecithin containing unsaturated fatty acid residue; instant claims 1, 12), as evidenced by Lipoid at pages 1 and 2.
Knoch does not anticipate the instant claims because it does not disclose a specific amount of sucrose in the lyophilized composition.
Wong relates to lyophilized liposome formulations [title] and discloses “the invention comprises a method of preparing a lyophilized liposome composition comprising preparing a liposome composition comprised of an unsaturated lipid, a hydrophobic drug associated with the liposome, and a cryoprotectant at a selected concentration. […] The liposome composition is then lyophilized” [0015]. Unsaturated lipids include phosphatidyl choline [0024]. Hydrophobic drugs, which “are typically localized in the bilayer core” (i.e., instant claim 8) [0047], include cyclosporine A [0050]. Suitable cryoprotectants include sucrose and suitable amounts of cryoprotectant range from 5% to 25% [0060]. Wong also discloses the weight “ratios of lipid to cryoprotectant include 2:1 to 1:100” [0062].
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 included the lyoprotectant (cryoprotectant) sucrose of Knoch in the amounts Wong teaches are suitable for protecting liposomes during lyophilization. One would have been motivated because where Knoch lacks guidance regarding the specific amount of lyoprotectant (cryoprotectant), Wong provides specific parameters for effective protection during lyophilization. One would have had an expectation of success because the liposomal compositions of Wong are similar to Knoch in that both compositions are lyophilized and may comprise an unsaturated phospholipid, a hydrophobic active agent (e.g., cyclosporine A) and lyoprotectant sugar (e.g., sucrose).
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 and Wong. 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 prior art 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.
One of ordinary skill in the art would have appreciated that this combination of Knoch, Wong and Keller encompasses a composition comprising 100-150mg/ml sucrose (e.g., 10-15% sucrose at a lipid to cryoprotectant ratio weight ratio of 1:2 to 1:3, as taught by Wong), 5mg/ml cyclosporin, 50 mg/ml phospholipid and surfactant (phospholipid and the nonionic surfactant to the ciclosporin of 10:1, as taught by Keller). 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, Wong and Keller would have encompassed a lyophilized composition comprising about 64.5-73.2% w/w sucrose, about 2.4-3.2% w/w cyclosporin A, about 22.0-29.0% w/w phospholipid (soybean lecithin) and about 2.4-3.2% 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 sucrose lyoprotectant (50-75% w/w and 65-70% w/w; instant claims 1 and 31), cyclosporin A (2-4% w/w; instant claim 10), 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 amounts taught by the prior art, e.g., 64.5-73.2% w/w sucrose, 2.4-3.2% w/w cyclosporin A, 22.0-29.0% phospholipid and 15:1 – 9:1 phospholipid to nonionic surfactant. Accordingly, a prima facie case of obviousness exists for the ranges of instant claims 1, 10, 13, 15 and 31.
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 composition comprising sucrose and a liposomal structure of cyclosporine A, lecithin containing unsaturated fatty acid residues (Lipoid S100) and a polysorbate solubility enhancer (polysorbate 80), wherein each component is present within the instantly claimed amounts (instant claim 1, 10, 11, 13, 15 and 31). Wherein the liposome are present at least partly in a unilamellar form and comprise an inner lumen surrounded by a phospholipid bilayer (unilamellar liposome; instant claims 3-5). Wherein the cyclosporine A is at least partially incorporated in the bilayer membrane (instant claim 8). Wherein the lecithin containing unsaturated fatty acid residues is a soybean phospholipid with >/= 94.0% phosphatidylcholine content (claim 12).
Finally, “[a] chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” MPEP2112.01 (II). Accordingly, since the prior art composition contains substantially the same components, i.e., lyophilized unilamellar liposomes of cyclosporine A, unsaturated phospholipids and polysorbate with sucrose, in the same relative proportions as instantly claimed, it would be expected to inherently possess the same chemical and physical properties, such as the inner lumen of the liposome forming structures being at least partially dehydrated (instant claim 6), and having the same dissolution and storage properties (instant claims 32 and 33).
While instant claim 6 is understood to inherently result from the lyophilization steps disclosed in the prior art, purely arguendo dehydrating the inner lumen of the liposome would have also been obvious in view of the prior art. Wong discloses liposomes of unsaturated phospholipids “cannot be stored for sufficiently long periods of time as aqueous suspensions because of hydrolysis of the lipids. Thus, long term storage of liposomes may require lyophilization of the liposome formulation” [0003-4].
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)). In the present case, a skilled artisan would have been motivated to optimize the lyophilization to remove all possible water from the liposomal composition, including water within the liposomes, because Wong teaches water negatively impacts stability. One would have had an expectation of success because Knoch desires lyophilized compositions.
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 the lyophilized composition as discussed above and taught by Knoch, Wong and Keller wherein the inner lumen of the liposome is at least partially dehydrated.
Regarding instant claim 7, Wong discloses “[i]n a preferred embodiment, the cryoprotectant is included in both the internal and external media. In this embodiment, the cryoprotectant is available to interact with both the inside and outside surfaces of the liposomes membranes. Inclusion in the internal medium is accomplished by adding the cryoprotectant to the hydration solution for the liposomes” [0061].
It would have been obvious to one of ordinary skill in the art, before the effective filling date of the claimed invention, to have included the lyoprotectant (sucrose) in both the internal and external media of the liposome compositions taught by Knoch, Wong and Keller, as discussed above. One would have been motivated because Wong teaches it is preferable to have the lyoprotectant (cryoprotectant) interact with both the inside and outside surfaces of the liposome membrane. One would have had an expectation of success because Wong discloses how to include the lyoprotectant inside the liposome. Additionally, in combining these elements one would have expected nothing more than predictable results because, when combined by known methods, each prior art element would have performed the same function as it had separately. See MPEP 2143, Exemplary Rationale A.
Regarding instant claim 30, the exemplary compositions of Knoch further comprise disodium edetate, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate monohydrate (i.e., one or more further excipients) [p. 18, lines 7-10]. Knoch also discloses lyophilizing a liquid aqueous formulation [p. 19, lines 18-20].
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, before the effective filling date of the claimed invention, to have combined the additional excipients and lyophilized a liquid formulation as taught by Knoch because Knoch discloses both are suitable for the compositions disclosed therein.
Furthermore, as discussed above, the prior art teaches a range of about 64.5-73.2% w/w sucrose in the lyophilized composition which overlaps with the instantly claimed range of 50-80% w/w and so a prima facie case of obviousness exists. 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, before the effective filling date of the claimed invention, to have formulated the lyophilized composition taught by Knoch, Wong and Keller, as discussed above, wherein the composition comprises one or more additional excipients and is obtainable by lyophilizing a liquid aqueous formulation.
While the properties of instant claim 33 are understood to be inherent to the prior art compositions, purely arguendo claim 33 is also obvious over the prior art. Wong discloses the “dehydrated or lyophilized formulations are suitable for extended storage. The formulation is stably storable for at least about 1-24 months” [0063]. Wong also exemplifies storage at 40 deg. C [0090].
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)). Given Wong desires stable storage for 1-24 months a skilled artisan would have been motivated to optimize the storage stability over 1-24 months.
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 the composition taught by Knoch, Wong and Keller, as discussed above, to be stable for at least 12 months as presently claimed.
3) Claims 8 and 9 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 Wong et al. (US 2006/0110441 A1, publication date 05/25/2006) and Keller et al. (US 9,161,963 B2, date of patent 10/20/2015), as evidenced by Lipoid (Unsaturated Phospholipids, Lipoid, retrieved 9/29/26, https://lipoid.com/en/products/natural-phospholipids/unsaturated-phospholipids/), as applied to instant claims 1, 3-8, 10-13, 15, 30-33 above, and in further view of Rahman et al. (WO 90/00389, publication date 01/25/1990).
Knoch, Wong and Keller, which are taught above, differ from the instant claims insofar as they do not teach the incorporation rate of cyclosporine into the liposome.
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 [p. 6, lines 4-5]. Rahman also discloses the composition may comprise sucrose as a cryoprotectant [p. 8, lines 3-6]. 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, Wong and Keller. One would have been motivated to do so because Rahman teaches that at least 95% encapsulation is an acceptable range for a liposomal cyclosporin compositions. 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, the instantly claimed range for cyclosporin incorporation of at least 90% (instant claims 8-9) overlaps the range of the prior art range (95-100% into the lipid bilayer) and so a prima facie case of obviousness exists. 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).
Response to Arguments
1) On page 10 of their Remarks, Applicant argues Knoch does not teach or suggest the instantly claimed amounts of lyoprotectant sugars.
This argument is not persuasive. In the absence of unexpected results, the instantly claimed ranges would have been obvious in view of the prior art, as discussed above.
2) On pages 10- 11 of their Remarks, Applicant argues that Knoch teaches away from the present claims because the addition of the lyoprotectant occurs in an unknown amount and only after formation of the liquid liposomal composition, stating “the present disclosure teaches that the chosen lyoprotectant is added prior to the formation of liposomal structures and, accordingly, can be incorporated or even encapsulated in the liposomal structures during their formation”.
This argument is not persuasive. The prior art does not criticize, discredit or otherwise discourage the solution as instantly claimed and therefore does not teach away from the instantly claimed formulations. See MPEP 2123. There is nothing directly stated in Knoch that would have discredited or discouraged the solution as claimed therefore this argument has not been found persuasive.
Additionally, the Examiner will respectfully note that the features upon which applicant relies (i.e., lyoprotectant sugars inside the liposome) are not recited in the rejected independent claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the present case the independent claims do not require lyoprotectant sugars inside the liposomes and when it is required by the dependent claims, the limitation is addressed by Wong which specifically desire interior lyoprotectants (cryoprotectants) (see Wong at para. [0061]).
3) On page 11 of their Remarks, Applicant asserts that including lyoprotectant sugars inside the liposome results in unexpected solubility and stability. Applicant cites the Inventor Declaration filed on March 11, 2026 (hereinafter “Declaration”) and Examples 5 on page 56 of the instant specification.
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) Applicant has not compared stability and dissolution to the closest prior art, which is Knoch at Example 2 on page 19, which is discussed in the rejection statements above.
(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 results to not appear to be in fact unexpected over the prior art. For example, Wong prefers interior and exterior cryoprotectant (lyoprotectant) because “the cryoprotectant is available to interact with both the inside and outside surfaces of the liposomes membranes” [0061]. A skilled artisan would have reasonably understood the greater interaction of the cryoprotectant with the liposome disclosed by Wong to mean greater cryoprotection. See also Cabral-Lilly et al. (US 20140255475 A1, publication date 09/11/2014). Cabral-Lilly relates to “[l]yophilized liposomal formulations with two or more encapsulated drugs” [abstract] and discloses “[f]ailure to include a cryoprotectant in the liposome interior has been shown to result in a loss of liposome integrity upon reconstitution, particularly with regard to retaining an encapsulated agent” [0009].
With respect to dissolution rate, the Examiner cannot determine if the results are truly unexpected because Applicant has not compared the allegedly unexpected result to the closest prior art, i.e., Example 2 of Knoch (see Knoch at page 19).
(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 are not commensurate in scope. The independent claims do not require lyoprotectant sugar inside the liposome. The evidence for dissolution rate on pages 5-6 of the Declaration do not disclose the weight percents of the disaccharide, the membrane forming substance and solubility enhancing substance and so the Examiner is not able to determine if the claims are commensurate in scope.
4) On page 12 of their Remarks, Applicant argues that “It is known to skilled artisans in the field of lyophilization that it is entirely unpredictable which lyoprotectant
(from the available broad variety of potential lyoprotectants) as well as which amount of such lyoprotectant (from the infinite amount of potential concentration ranges of lyoprotectants) would adversely interfere with the further constituents of the composition to be lyophilized” and so it would not have been obvious to arrive at the instantly claimed compositions from the disclosure of Knoch which does not include an amount of lyoprotectant and includes mannitol as a lyoprotectant.
This argument is not persuasive. While Knoch discloses mannitol, the preferred lyoprotectant is sucrose [p. 9, line 21] which is used in the example compositions [p. 19, line 18]. Additionally, “[a]rguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.” See MPEP 716.01(C)II. In the present case Applicant has not provided support that the field of lyophilization is so unpredictable that successfully formulating the instantly claimed lyophilized liposomal would have been unexpected.
5) On page 12 of their Remarks, Applicant argues that the teaching of Hua cannot be applied to Knoch because the active agents of Hua are structurally different than the cyclosporine of Knoch.
This argument is moot in view of the new rejections set forth above.
6) On page 13 of their Remarks, Applicant argues a skilled artisan would have been discourage from selecting the instantly claimed amounts of disaccharide because such a large amount of disaccharide would have potential negative effects such as impacting the nebulization process, increasing patient inhalation burden by diluting cyclosporine A concentration, aggregating or damaging liposomes, or triggering adverse effects especially when administering to a diabetic patient.
This argument is not persuasive. The prior art does not criticize, discredit or otherwise discourage the solution as instantly claimed and therefore does not teach away from the instantly claimed formulations. See MPEP 2123. There is nothing directly stated in Knoch that would have discredited or discouraged the solution as claimed therefore this argument has not been found persuasive.
Furthermore, in optimizing the sucrose content of the composition, as discussed in rejection statement “1)” of this office action, a skilled artisan would have understood that any changes to the formulation would impact the properties of the composition. It is not beyond the ability of a skilled artisan to adjust, for example, the dilutions, starting content of lyophilized liposomes, and administration frequencies of the lyophilized composition.
Regardless, the prior art teaches a high sugar to lipid ratio (see Wong at paragraph 62; “ratios of lipid to cryoprotectant include 2:1 to 1:100”) and so a skilled artisan would have been motivated to, and had an expectation of success in including sucrose in relatively large amounts.
7) On pages 13 to 14 of their Remarks, Applicant argues that “The Examiner's reliance on the range-criticality case In re Hill is misplaced because Hill involved a known range I operating space disclosed in the primary reference Carter and a selection of a narrower claimed range. Here, there is no known range I operating space disclosed
in the primary reference Knoch at all”.
This argument is not persuasive. The MPEP states: 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 shown sufficient number of tests outside the allegedly critical range. Specifically, applicant has not provided evidence for compositions comprising disaccharides in amounts greater than the claimed range. See, paragraphs 12-14 of the Declaration (filed 03/11/2026). There is no evidence that liposome structures having a mean particle size suitable for inhalation are not obtained when the concentration of disaccharide is greater than 67% w/w in the lyophilized composition. Accordingly, the Examiner is not able to determine if the claimed ranges are truly critical to the function of the invention, regardless of the prior art range.
8) On page 14 of their Remarks, Applicant argues saccharose, trehalose and lactose in the instantly claimed amounts demonstrate unexpected results. Applicant cites the Declaration which demonstrates that lyophilized compositions comprising 51, 61, and 67 wt.-% (w/w) of saccharose, trehalose, or lactose produced opalescent colloidal solutions of liposomally solubilized cyclosporine A, indicating the formation of liposome structures having a mean particle size suitable for inhalation. Applicant argues the failure of saccharose, trehalose, or lactose compositions having a 34 wt.-% (w/w) content and mannitol compositions having a 34, 51, 61, and 67 wt.-% (w/w) to produce an opalescent colloidal solution, i.e., liposome structures having a mean particle size suitable for inhalation, demonstrates the instantly claimed range of saccharose, trehalose and lactose provides the unexpected result of liposome structures having a mean particle size suitable for inhalation upon reconstitution.
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 is Knoch at 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]. Therefore, Knoch discloses a lyophilized composition comprising sucrose and a liposomal structure comprising cyclosporine A, lipoid S100 (i.e., soybean phospholipid) and a polysorbate which produces a compositions suitable for inhalation upon reconstitution.
(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 Applicant has not provided data for compositions comprising the claimed disaccharides in amounts above the claimed range. Additionally, the Examiner will respectfully note that Applicant has not provide a sufficient number of tests below claimed range. It is not clear if the claimed lower limit of 50% w/w disaccharide is truly critical given the evidence compares compositions comprising 51% w/w which are suitable for inhalation to compositions comprising 34% w/w disaccharide which are unsuitable for inhalation. In other words, it is not clear where between 51% w/w and 34% w/w the critically lower limit truly lies.
(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 are not commensurate in scope with the evidence because the instant claims do not recite a sugar to lipid ratio which is important for stability according to Wong at paragraph 61. Additionally, the narrow recitation of compositions comprising specific amounts of cyclosporine A, polysorbate 80 and phospholipid does not reasonably support compositions comprising any amount of cyclosporine A, polysorbate 80 and phospholipid, as instantly claimed.
The claims also do not require reconstitution by a specific “fixed small volumes” and specific amount of lyophilized composition which appears to be important to the alleged criticality of the claimed range. For example, in the second full paragraph on page 14 of their Remarks applicant alleges that disaccharides in amounts of 79% w/w of the lyophilized composition would be unsuitable for nebulization due to high viscosity of the reconstituted solution comprising 20% w/w (18.5% w/v) sucrose, as evidenced by Ghazanfari and Telis (cited in the Information Disclosure Statement filed 09/04/2026). However, there is nothing in the instant claims which requires specific dilution (reconstitution) parameters of the lyophilized composition and so lyophilized compositions comprising 79% w/w sucrose would not necessarily result in a 20% w/w (18.5% w/v) solution of sucrose, as alleged by Applicant.
9) On page 15 of their Remarks, Applicant argues the secondary references do not remedy any of the deficiencies of the prior art alleged by applicant.
This argument is not persuasive for the reason above and of record.
Conclusion
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/C.T.W./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
