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 .
Election/Restrictions
Applicant's election with traverse of Group II, claim 10, drawn to a method of making a product; and the species corresponding to IX Preparation Method in the reply filed on December 15, 2025, is acknowledged. The traversal is on the ground(s) that the method of making a product claim is not materially different in scope and that there is no search burden to examine all of the claims together. This is not found persuasive because the test for distinct inventions is whether the product, method of making the product as claimed, can be used in a materially different process. The product and method of treating require different search strategies than the method of making the product. In the instant case, the product could be used in treating diseases from lacrimal dysfunction syndrome with gastroesophageal reflux disease, dry eye syndrome, or another disease or symptom, which is different than the method of making the product of Group II.
The requirement is still deemed proper and is therefore made FINAL.
The species of method of group II, therefore claims 10 and 18-24 which read on the elected species has been considered.
Claims 1-9 and 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 15, 2025.
Priority
This application is a 371 National Phase of International Application NO. PCT/IB2021/054572, filed on 05/26/2021, and claims foreign priority to Italian Application No. 102020000012370 filed on 05/26/2020.
Status of Claims
Claims 1-8, 10-13 and 19-26 are pending.
Claims 1-8 and 11-13 were withdrawn from consideration; Claims 9 and 18 are canceled; and Claims 25 and 26 are added new.
Claims 10 and 19-26 are under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 13, 2025, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objections/Rejections Withdrawn
Objections and/or rejections not reiterated from previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 (modified)
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.
Claims 10, 18, 19, 25, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008/039984 (published 04/03/2008, on IDS filed 11/16/2022) in view of WO 1994/24150 (published 10/27/1994), and further in view of Pepstatin A, Sigma-Aldrich (hereafter “Sigma-Aldrich”) (published 3/19/2001).
WO’984 teaches that pepstatin is a powerful inhibitor of aspartyl proteases including pepsin (see [0005]). WO’984 identifies that pepstatin can be utilized to treat diseases and disorders related to aspartyl proteases (see [0004]), and could be formulated with pharmaceutical excipients to form pepstatin-containing eye drops (see [0033], [0043], [0045]).
It is already known in the art that pepstatin A is a low molecular weight inhibitor of aspartyl proteases, including pepsin, cathepsin D, renin, etc. WO’984 teaches the composition containing cathepsin D inhibitor is pepstatin A or a salt (see Claim 2). WO’984 discloses a process for preparing medicinal products which can be used in the treatment of cathepsin D-related conditions, consisting in mixing pepstatin or the pharmaceutically acceptable salts of this compound with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants (page 10, [0052]). WO’984 further specifies that for liquid compositions, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs may be used, containing inert diluents such as water, ethanol (see [0048]). WO’984 discloses mixtures of pepstatin A were made by creating a 5 mM solution of pepstatin A in 95% ethanol (e.g. an alcoholic solution of pepstatin at a neutral pH) (see Example 1, [0062]).
WO’984 is silent specifically about the aqueous solution composition comprising alginic acid salt.
WO’150 comprises invention in the field of pepstatin analog proteinase inhibitors, more particularly proteinase inhibitors for use in the treatment and prevention of infections in plants and animals (see page 1, line 9-13). WO’150 teaches the proteinase inhibitors may be applied as a suspension or dispersion, e. g. as an aqueous suspension with a suitable protectant such as alginate, magnesium silicate, etc. (see page 23, line 5-9).
Sigma-Aldrich teaches Pepstatin A product description and preparation instructions. Sigma-Aldrich teaches Pepstatin A is an inhibitor of acid proteases (aspartyl peptidases); it forms a 1:1 complex with proteases such as pepsin, renin, cathepsin D (left col, paragraph 1); It can be dissolved at 1 mg/mL in 10% (v/v) acetic acid in methanol (9:1 methanol:acetic acid) (see left col, paragraph 3).
Examiner’s Note: This is in correlation with the instant specification which states that at neutral pH (buffered) pepstatin is in acidic form and it can be dissolved in alcohol (for example ethanol) and then diluted in water (see instant page 5, line 9-11).
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to combine the mixture comprising of pepstatin and alginic acid or a salt derivative in an aqueous composition as taught by WO’150 with an alcoholic solution containing pepstatin as taught by WO’984 and Sigma-Aldrich to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because it would predictably lead to a combined product having the same predicted and expected utility, namely eye drops usable to further reduce pepsin in the eye following administration as eye drops. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Regarding claim 10, US’984 teaches that the medicinal products consist at least of pepstatin, in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicinal products according to the invention may be employed orally, cutaneously, transdermally, nasally, as eye drops (see page 8, [0045]). US’984 further specifies for sterile compositions administration, preferably be solutions, aqueous or non-aqueous, suspensions or emulsions, as a solvent or vehicle, water, alcohols, etc. may be employed (see [0049] and [0050]).
Regarding claims 18 and 19, WO’984 teaches the solutions were diluted to 150 mM for use in efficacy studies (see Example 1, [0062]). At the time before the effective filling date of the claimed invention, it would have been obvious to use solvent as ethanol and as specified “expected amount of pepstatin in the composition: less than or equal to 1 pM” because the claimed range overlaps with and within the range disclosed by WO’984.
Regarding claims 25 and 26, Sigma-Aldrich teaches that pepstatin A can be dissolved at 1-2 mg/ml in ethanol (right col, paragraph 1); heat may be required for complete solution, and solutions of Pepstatin A can be heated as high as 60 °C without any decomposition of the peptide (right col, paragraph 1). Sigma-Aldrich specifies the solubility of Pepstatin A:it is insoluble at any concentration in methanol or DMSO; it can be dissolved at 1 mg/mL in 10% (v/v) acetic acid in methanol (9:1 methanol:acetic acid). The inclusion of acetic acid is necessary to dissolve this peptide in methanol (see left col, paragraph 3). Sigma-Aldrich also specifies stock solutions at 1 mg/mL should be stable at least a week at 4 °C; a 1 mM solution in methanol should be stable for months at –20 °C; and an effective working concentration is 1 µM; a typical working concentration is 0.5-1.0 µg/mL (right col, paragraph 2-3).
Examiner’s Note: Applicants’ selection of species corresponding to IX Preparation Method in the instantly claimed invention has similar experimental/preparation conditions as provided by Sigma-Aldrich. With the exception of using the acidic component, i.e., the instantly claimed invention specifies use of boric acid (instead of acetic acid for dissolution of pepstatin A as mentioned by Sigma-Aldrich). As it is known in the art about the use of boric acid in eye drops or eye medications (See Gupta_2003), it can be obviously used in place of acetic acid.
Claims 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008/039984 (published 04/03/2008, on IDS filed 11/16/2022) in view of WO 1994/24150 (published 10/27/1994) and Pepstatin A, Sigma-Aldrich (hereafter “Sigma-Aldrich”) (published 3/19/2001), as applied to claims 10, 18, 19, 25, and 26 above, and in further view of US 8,501,822 (published 08/06/2013).
The teachings of WO’984, WO’150, and Sigma-Aldrich are discussed above. However, they are silent specifically about the use of hyaluronic acid or a pharmaceutically acceptable salt and the formulation for diluted solution as eye drops as claimed.
US’822 teaches the ophthalmic composition contains alginic acid and/or a salt in combination with hyaluronic acid and/or a salt (see Abstract). US’822 teaches in the ophthalmic composition, a single type of alginic acid and salts may be used, or any combination of two or more types may be used. (see page 7, col 7, line 35-36). US’822 teaches the ophthalmic composition also comprises at least one member selected from the group consisting of hyaluronic acid and salts (see page 7, col 7, line 64-67). US’822 specifies examples of the hyaluronic acid salt include salts with an alkali metal, such as sodium or potassium; salts with an alkaline earth metal, such as calcium or magnesium; and salts with a metal (see page 7, col 8, line 32-35). US’822 teaches the pH of the ophthalmic composition is not particularly limited, so long as it is within a pharmacologically or physiologically acceptable range; more preferably from 6 to 8 (see page 8, col 10, line 11-16; see neutral pH conditions in Test Examples 1 and 3; Tables 1, 3, 8, and 9). US’822 discloses the ophthalmic composition is in a liquid or gel form, and preferably is in a liquid form. Preferable embodiment of the ophthalmic composition is an aqueous ophthalmic composition (see page 8, col 10, line 1-6). US’822 further teach the ophthalmic composition is an eye drop, an eye wash, or a wetting and rewetting drop (see page 5, col 3, line 16-18).
At the time before the effective filing date of the claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to use the formulation at neutral pH specifically for use as eye drops taught by WO’822 in diluted alcoholic solution containing pepstatin as taught by WO’984 and Sigma-Aldrich to arrive at the presently claimed invention. The artisan of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because it would predictably lead to a combined product having the same predicted and expected utility, namely eye drops usable to further reduce pepsin in the eye following administration as eye drops. It is prima facie obvious to substitute equivalents known in the art for the same purpose. MPEP §2144.06.
Regarding claim 22, US’822 teaches the ophthalmic composition of the invention exhibits a longer retention of mixed components, such as hyaluronic acid and/or a salt thereof, and other pharmacologically active ingredients, on an ocular mucosa (page 6, col 6, line 23-27). US’822 specifies in order to prepare the ophthalmic composition in a desired form, various components and additives can be appropriately selected and mixed singly or in any combination in the ophthalmic composition by a conventional method, as long as the effects of the present invention are not impaired. As the component and the additive, various additives are pharmaceutical excipients (page 9, col 11, line 27-34).
Regarding claims 23 and 24, US’822 teach about the ophthalmic composition of the invention is used in the form of an eye drop, an eye wash, a wetting and rewetting drop (page 9, col 11, line 46-49).
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filling date.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2008/039984 (published 04/03/2008, on IDS filed 11/16/2022) in view of WO 1994/24150 (published 10/27/1994) and Pepstatin A, Sigma-Aldrich (hereafter “Sigma-Aldrich”) (published 3/19/2001), as applied to claims 10, 18, 19, 25, and 26 above, and in further view of WO 2018/215897 (published 11/29/2018).
The teachings of WO’984, WO’150, and Sigma-Aldrich are discussed above. However, they do not teach specifically about using alginate salt is magnesium alginate as claimed.
WO’897 teaches the use of alginate salt, more preferably magnesium alginate in the composition (see Claim 8). WO’897 specifies ophthalmic solution comprises, component % by weight/total weight - Magnesium alginate (see Experimental section, and Compositions on pages 11-13). It would have been prima facie obvious to combine the teachings of US’897 with WO’984, WO’150 and Sigma-Aldrich before the effective filling date of the claimed invention by considering use of magnesium alginate as a stable component in the aqueous medium to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to utilize magnesium alginate to produce improved ophthalmic grade eye drops as taught in WO’897.
Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filling date
Response to Arguments
Applicant’s arguments filed 7/15/2026 have been fully considered but they are not persuasive in view of the modified grounds of rejected necessitated by amendment.
Applicant argues as understood in the art, pepstatin is insoluble in water and alginate is insoluble in alcohol. Thus, the skilled person would believe that simply combining the alcoholic composition of WO2008/039984 with the aqueous composition of WO 1994/24150, as articulated in the Office Action, would likely cause the pepstatin and/or the alginate to fall out of solution. The skilled person would also recognize that precipitated solid particles would be undesirable in an ophthalmic formulation intended to be administered to the eyes. Therefore, the skilled person would have no motivation to combine the compositions of WO 2008/039984 and wo 1994/24150 to arrive at a formulation for ophthalmic use. Applicant argues and encloses a reference Sijin, et al. providing evidence of unpredictability, which teaches, e.g., that "an organic solvent, mainly ethanol is added into the sodium alginate solution to reduce the alginate solubility and therefore precipitate sodium alginate". Examiner would like to bring to Applicant’s notice that the reference Sijin et. al. teaches the development of the conventional and alternative processes for alginate extraction from brown seaweed (see Abstract). Sijin et. al. teaches about the alginate extraction, production, and industrial application. Aforementioned process of alginate extraction is incommensurable with preparation of ocular therapeutics.
Examiner reminds the Applicant that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). 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). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). The Examiner would like to remind the Applicant that it is known in the art that Alginates formed with divalent cations are insoluble; calcium and magnesium alginates do not dissolve in water (see Alginates_USDA_2015 report, line 158-159). Also, extensive studies have already been performed regarding the viscosity of alginate-based ocular therapeutics. Examiner would like to bring to the Applicants’ notice a study by Hermansson et. al. studies where the influence of the mixture of water and alcohols on the solubility and properties of alginate (see Abstract) is taught. The solvent quality of water with increasing amounts of ethanol (0–20%) on alginate was studied using intrinsic viscosity (see Abstract). Hermansson et. al. teaches ethanol as a co-solute is interesting from a wound care perspective, primarily because of the antiseptic effect of this solvent, but it is also of interest for the food and beverage sector, as well as the pharmaceutical industry. In general, alcohols are used to decrease the solubility and to precipitate alginate, for example during extraction. The concentration of ethanol (in ethanol–water mixtures) required for 50% precipitation of the polymer has been studied and is dependent on the type of other ions present and their concentration in the mixture. An increasing concentration of mono- or di-valent ions lead to precipitation of alginate at lower ethanol concentrations (see page 290, left col, paragraph 2). Hermansson et. al. show that the addition of low to moderate (up to 15%) concentrations of ethanol increases the intrinsic viscosity (extension) of alginate. The solvent quality is reduced at higher ethanol concentrations (20%) as reflected by a reduced intrinsic viscosity (see page 295, right col, paragraph 5). The instantly claimed invention uses
EtOH 1 mg/ml = from 0.01% to 1% (0.01%-0.1%) (w/w) (see instant specification [0076], Table 1], which is within the soluble range of divalent alginate (i.e., magnesium alginate in the instantly claimed invention). The Examiner has noted that the claims have no limitations on concentrations of solvent(s) used other than the concentration of active ingredient as stated in the newly added claim 25. As indicated in MPEP §2144.05(I): “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.”
Applicants’ argument of “to the extent that any further discussion is needed, Applicant would like to draw the Examiner's attention to the experimental section of present patent application (see, paragraph VII.C on page 16 of PCT application as published) showing tests on the combination pepstatin + magnesium alginate which were carried in order to check the presence of a synergistic effect of the combination pepstatin and magnesium alginate (compositions according to the invention) in totally inhibiting pepsin.” Examiner would like to remind the Applicant that in the Applicant's election with traverse of Group II, drawn to a method of making a product; and the species corresponding to IX Preparation Method in the reply filed on December 15, 2025. Therefore, the examination was performed with consideration of the claims 10 and dependent claims (19-26) and IX Preparation Method as an example.
With regard to Applicants claim, “the results of the experimentations are shown in Figure 5 of the application, which shows the absorption spectra….the synergistic effect of pepstatin and magnesium alginate made it possible to obtain a complete abatement of pepsin activity”. In the instantly claimed invention, FIG. 5 is relevant for Example VII.C. (which is not an elected species), and moreover, there is no exceptional synergistic effect seen in FIG. 5 (see x-axis values of the instant figures). Examiner would like to remind the Applicant "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991).
Prior Art of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gupta (“Acute Eye Conditions”; Emergency Medicine; MJAFI; 59; No: 3; 239-241; published 2003).
Alginates_USDA_2015 (“Alginates Handling/Processing”; Technical Evaluation Compiled by OMRI for the USDA National Organic Program; page 1-23; published February 5, 2015).
Hermansson et. al. (“Impact of solvent quality on the network strength and structure of alginate gels”; Elin Hermansson, Erich Schuster, Lars Lindgren, Annika Altskär, Anna Ström; Carbohydrate Polymers 144 (2016) 289–296; published February 24, 2016).
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
