Claims 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 .
Claims 1-6, 8, 10, 12-23, 26, 29 and 30 ae presented for examination.
The amendments and remarks filed on 12/05/2025 have been received and entered.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 8, 10, 12-23, 26, 29 and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Kaye et al. (US 20130324574) in view of Aberg et al. (US 20170105987) and further in view of Shantha et al. (US 20110052678).
Kaye teaches a method of treating a subject suffering from an ocular inflammatory disease (OID),
uveitis, bacterial conjunctivitis, viral conjunctivitis, an inflammation of the orbital tissue, the lacrimal
apparatus, the eyelid, the cornea, the retina or the optic pathway. Kaye teaches a method for treating a
subject suffering from an autoimmune disease-associated ocular inflammation comprising periodic
ocular administration to the subject a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt, and an ocular pharmaceutical composition comprising laquinimod or a
pharmaceutically acceptable salt thereof for use in treating an autoimmune disease-associated ocular
inflammation. See the abstract. The method comprising periodic administration to the subject of a
therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof effective
to treat the subject. See para [0015]. The laquinimod or pharmaceutically acceptable salt thereof is
administered topically or orally. See para [0020]. The use of an eye drop is taught in Para [0031]. The
concentration of laquinimod or pharmaceutically acceptable salt thereof in the liquid or gel is 0.5% (5
mg/ml)-10.0% (100 mg/ml). See para [0022]. The pH of 7.3-7.4 is taught in Para [0098]. The
laquinimod in a gel or liquid form is taught in claim 9. The use of polymers, such as, carbomers and cellulose is taught in Para [0037].
Kaye differs from the claimed composition in the presence of some of the secondary components. Aberg teaches the use of norketotifen for the treatment of intraocular pressure, Para [0008]. The use of EDTA is taught in Para [0022]. The concentration of the chelating agent is taught to be in amounts of about 0.01 wt. % to about 10 wt. %, specifically about 0.01 wt. % to 2.0 wt. %. See Para [0022]. The use of stabilizers and solubilizers is taught in Paras [0023] and [0024]. Aberg teaches that exemplary stabilizers that are compatible with norketotifen include methylcellulose, edetate, chitosan,
Hydroxypropyl methylcellulose and hydroxyethyl cellulose, para [0023]. Aberg teaches that stabilizers listed here are useful in concentrations of about 0.05 wt. % to about 4 wt. %, and are specifically used in
concentrations of about 0.05 wt. % to about 2 wt. %. See Para [0023]. Aberg teaches that EDTA
functions as a chelating agent and a stabilizer, Para [0023]. The use of solubilizers is taught in Para
[0024]. The use of a buffering agent to keep the pH about 4-6 is taught in Para [0025]. Aberg teaches
that the Tonicity-adjusting agents increase the effective osmolarity or effective osmolality of a
formulation. Ocular compositions may contain a tonicity-adjusting agent in an amount sufficient to
cause the final composition to have an ophthalmically acceptable osmolality (generally about 150 to
about 450 mOsm and preferably about 230 to about 330 mOsm). Exemplary tonicity-adjusting agents
to be used with norketotifen may be of ionic and/or non-ionic type. An example of ionic type tonicity
enhancers is sodium chloride and examples of non-ionic tonicity enhancing agents are, for example
sorbitol and propylene glycol, which are compatible with norketotifen. Thus, norketotifen formulations
may include, for example sodium chloride, in amounts of about 0.1 wt. % to about 0.9 wt. %, sorbitol in
amounts of about 0.1% to about 10%, or propylene glycol in amounts about 0.1 wt. % to about 10 wt. %.
See Para. [0026]. Aberg teaches that Ophthalmic solutions may contain one or more viscosity-adjusting
agents and have a viscosity of about 1.0 to about 100,000 cP, specifically about 2.0 to about 90,000 cP,
and more specifically about 2.5 and about 75,000 cP. See Para.[0027]. Aberg teaches that Viscosity
modifying agents that are compatible with norketotifen include edetate, methylcellulose,
carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene glycol,
propylene glycol alginate, chitosan, and tragacanth, Para. [0027]. Exemplary of the humectants that are
compatible with norketotifen include polyethylene glycol, sorbitol and propylene glycol. Humectants
are used in amounts of about 0.05 wt. % to about 10 wt. %, specifically about 0.1 wt. % to about 4 wt. %,
and more specifically about 0.1 wt. % to about 2 wt. %. See Para [0028]. The use of antioxidants is
taught in Para [0029]. Exemplary lubricants that are compatible with norketotifen include
methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, thiolated acrylic acid polymers, carbomer, carboxymethylcellulose sodium, chitosan, and polyisobutylcyanoacrylate When used, the
amount of lubricant is about 0.1 wt. % to about 10%, specifically about 0.1 wt. % to about 4 wt. %, and
more specifically about 0.1 wt. % to about 2 wt. %. See Para [0033]. The use of surfactants, such as
polysorbates is taught in Para [0035]. The concentrations of the surfactants is taught to be in amounts
of about 0.05 wt. % to about 4 wt. %, specifically about 0.1 wt. % to about 2 wt. %. See Para [0035].
The composition being in a gel, ointment and emulsion is taught in Para [0037]. The use of
preservatives, such as benzalkonium chloride at the concentration of 0.0001% is taught in Para [0039]
and [0040]. The treatment of patients having glaucoma is taught in Para [0055]. Aberg teaches that
Intraocular hydrophobic ointments may contain norketotifen at concentrations of about 0.02 wt. % to
about 1.0 wt. %. The intraocular hydrophobic ointments have a viscosity of about 1,000 to about
500,000 cP, specifically about 20,000 to about 200,000 cP. Ophthalmic hydrophobic ointments have
tonicity of about 150 and about 450 mOsm, specifically about 230 and about 330 mOsm. The intraocular
hydrophobic ointments can also contain other excipients, such as humectants, viscosity modifying
agents, tonicity agents, chelating agents, buffers, surfactants, mucoadhesive, antioxidants and
preservatives. The intraocular hydrophobic ointments and gels were designed for once-daily ocular
administration or for repeated ocular administrations from two to five times daily to a mammal in need
thereof. See Para [0092]. Aberg teaches that useful intraocular emulsions contained norketotifen at
concentrations of about 0.02 wt. % to about 1.0 wt. %. The intraocular emulsions had a viscosity of
about 1.0 to about 300,000 cP, specifically about 2.0 to about 90,000 cP, most specifically about 2.5 to
about 75,000 cP. The intraocular emulsions had osmolality of about 150 to about 450 mOsm,
specifically about 230 to about 330 mOsm. The intraocular emulsions had pH of about 4 to about 6.5.
The intraocular emulsions may also contain excipients, such as humectants, viscosity modifying agents,
tonicity agents, chelating agents, buffers, muco-adhesives, surfactants and antioxidants. If wanted, a
preservative can be added, however, no preservative will be needed when the concentration of norketotifen is greater than or equal to about 0.02 wt. % and the pH is about pH 4.0 to about pH 6.0.
See Para [0097].
Shantha teaches the treatment of macular degeneration with ophthalmic topical preparation using
insulin and/or IGF-1 and other therapeutics agents in an ophthalmic topical preparation. See para
[0099]. Shantha teaches that the penetration enhancers may include anionic surfactants, urea's, fatty
acids, fatty alcohols, teARMDenes, cationic surfactants, nonionic surfactants, zwitterionic surfactants,
polyols, amides, lactam, acetone, alcohols, and sugars. See para [0172]. The use of benzalkonium
chloride is taught in Para [0177]. Shantha teaches the pH can be within a range which the pH is
acceptable to ophthalmic preparations which the pH preferably is within a range from 4-6-7 to 8 most
preferably 7.4. See Para [0202]. Shantha teaches that buffering ingredients, such as sodium borate,
sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate,
triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate,
monothioglycerol, thiosorbitol, ethylenediamine tetracetic. Furthermore, appropriate ophthalmic
vehicles can be used as carrier media for the current purpose. This includes conventional phosphate
buffer vehicle systems which are isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic
sodium borate. See para [0213]. The use of polysorbate is taught in Para [0216]. The use of glycerin
and mannitol carboxy methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose and
polyvinyl alcohol at the concentration of 0.001% to about 10% is taught in Para [0217]. Shantha
teaches that stabilizing agents are antioxidants, like bisulfites and ascorbate. The metal chelating agents
like sodium EDTA and drug solubility enhancers which are the polyethylene glycols. See para [0218].
Shantha teaches that The ophthalmic compositions, which are intended for direct application to the eye,
will be formulated to have a pH and tonicity which these are compatible with the eye. This will normally
require a buffer to maintain the pH of the composition at or near physiologic pH (i.e., pH 7.4) which the buffer may require a tonicity agent to bring the osmolality of the composition to a level or near 210-320
millimoles per kilogram. See Para [0219]. The use of polysorbate is taught in Para [0224].
It would have been obvious to a person skilled in the art to add the claimed secondary components to
the ophthalmic formulation of Kaye comprising laquinimod motivated by the teachings of Aberg and
Shantha, which teach the use of the claimed secondary ingredients in ophthalmic formulations being
used for treating glaucoma and conditions with excess neovascularization as old and well known. To
house an ophthalmic formulation in a container is considered to be within the skill of the artisan. Aberg
and Shantha make clear that all the claimed secondary components have been previously used in
ophthalmic formulations.
Response to arguments
Applicant’s arguments have been noted. Applicant in his remarks argues that “Kaye may
disclose laquinimod eye drops, but Applicant asserts that Kaye does not disclose, and is
completely silent regarding, (a) the specific viscosity range as recited in present claim 1, (b) the mandatory use of a non-ionic tonicity agent, (c) the mandatory use of a C3-C6 polyol humectant,
or (d) any antioxidant. Indeed, Kaye may disclose only that the concentration of laquinimod in
the liquid or gel is 5 mg/ml -100 mg/ml and that pH may be 7.3-7.4 (Kaye paragraph [0022];
Kaye paragraph [0098]); however, Applicant asserts that Kaye never discloses anything about a
specific viscosity range in combination with the selection of the non-ionic tonicity adjusting
agent, humectant, antioxidant, and pH range as defined in present claim 1. It is noted that
although in paragraph [0037] Kaye mentions various excipients (including e.g., carbomers and
modified cellulose derivatives), Kaye is completely silent on any specific combination of
excipients and selected viscosity. In the in vivo examples performed by Kaye, laquinimod is used
as a solution in sterile water, cf. Kaye paragraph [0069]”. It is the examiner’s position that Kaye teaches the use of laquinimod in combination with the claimed polymers and a pH within the scope of the claimed pH. The use of components, such as, EDTA, polyol and the tonicity agents is taught by the secondary references to be as old in ophthalmic formulations. Applicant in his remarks further argues that “if anything, Applicant asserts that Aberg teaches away from such generalization, by pointing out that the excipients have been carefully selected for the specific active ingredient norketotifen. A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant.” It is the examiner’s position that Aberg does not discourage a person skilled in the art from using the ophthalmic carriers with other ingredients. There is no statement in Aberg that the carriers cannot or should not be used in other ophthalmic formulation. Furthermore, Shantha teaches the use of the claimed carriers in ophthalmic formulations as old and well known. Applicant in his remarks additionally argues that “Applicant's data demonstrate that laquinimod is chemically stable at pH ≥ 6.8, remaining >99 % intact after two weeks at 40 °C (Tables 47 and 48). Aberg's formulations, on the other hand, are optimized for norketotifen stability at pH ≤ 6.0. Aberg thus teaches away from the
claimed pH range. Critical viscosity limit.
Aberg teaches ophthalmic solutions "may contain one or more viscosity-adjusting agents
and have a viscosity of about 1.0 cP about 100,000 cP, specifically about 2.0 to about 90,000 cP,
and more specifically about 2.5 and about 75,000 cP." (Aberg, paragraph [0026]).” It is the examiner’s position that Kaye teaches a pH encompassing the claimed pH. Aberg’s viscosity of 1.0-100,000, encompasses the claimed viscosity of 2-50 mPas. Applicant in his remarks argues that “Tables 66 to 69 and FIGS. 15-18 of the present application show that, at equal laquinimod concentration, the claimed formulations increased the cumulative absorption of laquinimod in cornea about 1.7-2.9-fold versus saline (PBS) control. The Examiner cites no teaching or reasoned expectation that delivery would be enhanced in such a remarkable way by a formulation as presently claimed”. It is the examiner’s position that Kaye teaches the use of laquinimod in combination with the claimed polymers and at a pH within the scope of the claimed pH. Applicant’s side by side comparison is not done with the closest prior art and it is done with a saline solution. Applicant further argues that “the rejection relies on picking and choosing disparate teachings from three unrelated references, and then modifying each reference in a manner contrary to its core teachings. For example, in Aberg, raising the pH well above the pH required by Aberg, selecting a viscosity range far from the one specified as preferred by Aberg, omitting ionic tonicity agents as mentioned by Aberg, and substituting laquinimod for norketotifen. Moreover, for Shantha, substituting laquinimod for insulin or IGF-1, and picking specific excipients from a generic list. Applicant asserts that such hindsight reconstruction is impermissible”. Applicant’s attention is drawn to In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986), where the court states “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected”. In the instant case there is no evidence to the superior effect of the claimed composition over Kaye. In response to applicant’s arguments that the examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only Knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case Kaye, Aberg and Shantha teach all the components applicant has selected to formulate the claimed ophthalmic Composition. To select components disclosed by the prior art, being used in an ophthalmic formulation and use it for the same purpose is considered to be within the skill of the artisan in the absence of evidence to the contrary.
THIS ACTION IS MADE FINAL. 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 ZOHREH A FAY whose telephone number is (703)756-1800. The examiner can normally be reached Monday-Friday 9:30AM-6:00.
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/ZOHREH A FAY/Primary Examiner, Art Unit 1617