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 .
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: Stable Cross-linker Compositions for Eye Treatment.
The words listed below are not considered as part of the title of an invention, these words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues. The term "new" will not be deleted when it is a part of a proper name, such as "New York". Similarly, the term "design" will not be deleted when it is a part of a term, such as "Design-aiding apparatus...".
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Improvement(s) in/for/of
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Design for/of (a)
Ornamental design
Ornamental
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
Drawings
The drawings are objected to because Figure 2 has poor image resolution and thus it is difficult to read the text. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 6 is objected to because of the following informalities: the phrase "of from" is not correct grammar. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6, 8, 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 6, 8, 19, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
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 and 8-11, 16-20, 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over PATHAK (PATHAK et al., US 20140271897 A1, 2014-09-18, IDS) as evidenced by PubChem (PubChem, Bis(sulfosuccinimidyl) suberate, 2005-08-08) in view of Kumar (Kumar et al., Recent Challenges and Advances in Ophthalmic Drug Delivery System, THE PHARMA INNOVATION, Vol. 1 No. 4 2012).
The reference PATHAK teaches “In another embodiment, a crosslinker that can react in situ with the live tissue or bioprosthesis tissue to crosslink the tissue is used. The composition, preferably colored or fluorescent composition is injected using oscillating device described in this invention. Upon injection, the injected composition reacts with the extracellular proteins in the tissue under effective crosslinking conditions and forms effective crosslinks with the tissue. The crosslinked tissue can have different physical and chemical properties than unmodified tissue. Generally drugs and crosslinking agents cannot penetrate inside the eye when applied topically in the eye. The diffusional barrier is a natural protection for the eye to protect it from unwanted chemicals found outside the eye. The inventive compositions break this diffusion barrier mechanically by injecting the sustained drug delivery or tissue crosslinking compassions using an oscillating needle or multiple needles like devices. The oscillation and deposition depth in the cornea can be varied depending on the device parameters used. In the cornea, the crosslinking or drug delivery compositions may be deposited at a depth of 5-500 microns, preferably at a depth of 10-300 microns. The deposited compositions undergo crosslinking reaction with the cornea tissue and thus help to stabilize the cornea tissue”[0231] and “In a variation of above example, disulfosuccinimidyl suberate (DSS) solution (DSS concentration 20 mg/ml in PBS pH 7.2, 0.1 mg ml sodium fluorscein as colorant is infused in place of PEG10K4ARM glutarate NHS ester. This crosslinker produce biostable tissue in the infused area”[0358]. Pubchem (sections 2.4.1-2.4.2 and 1.1) provides evidence that DSS is a compound of the instant formula I (see below) and the compound named in claim 5. The reference Pubchem also provides evidence of the molecular weight of 528.5 g/mol (page 1). This mean the 20mg/ml= 0.038M.
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The reference PATHAK teaches “The crosslinker may be linear or branched in nature. The effective crosslinking conditions include: 10-100 mg/ml crosslinker concentration which may be dependent on molecular weight, pH 6-8, preferably pH 7.2 in biocompatible buffer like PBS, exposure time 1 minute to 12 h, preferably 30 minutes to 6 h”[0355] and “ In vitro degradation of the polymers is monitored gravimetrically at 37 degree C., in aqueous buffered medium such as, by way of example, and not limitation, phosphate buffered saline (pH 7.2)”[0263]. The reference Pubchem also provides evidence of the molecular weight of 528.5 g/mol (page 1). This mean the 100mg/ml= 0.19M.
This helps to teach claims 1-6, 8-11 and 23.
This also helps to teach claim 16 because it teaches “The inventive compositions break this diffusion barrier mechanically by injecting the sustained drug delivery or tissue crosslinking compassions using an oscillating needle or multiple needles like devices. The oscillation and deposition depth in the cornea can be varied depending on the device parameters used. In the cornea, the crosslinking or drug delivery compositions may be deposited at a depth of 5-500 microns, preferably at a depth of 10-300 microns. The deposited compositions undergo crosslinking reaction with the cornea tissue and thus help to stabilize the cornea tissue”[0231]. A needle puncture is a wound and it teaches the composition to stabilize the punctured tissue. The needle device also helps to teach claim 22.
The reference PATHAK teaches “Ophthalmic bioprostheses such as donated human cornea or animal tissue based cornea may also be infused with sustained releasing composition. Cornea could be also crosslinked in situ as described previously” [0248]. The phrase “to stiffen the cornea to make it more robust for suturing” is not given patentable weight because it simply expresses the intended result of a process step positively recited.
This helps to teach claim 21.
The reference PATHAK teaches “The crosslinking of live cornea tissue can potentially help to treat certain medical conditions such as Keratoconus. Or Keratectasia. The infusion of crosslinking agent using an oscillating needle can help to infuse tissue crosslinker in the cornea, in particular corneal stroma, without removal of corneal epithelium and can crosslink the corneal tissue in situ” [0231] and “A multi-needle injectable device where 5 to 10000 micro needles or more are arranged in the shape of a circle (needles are placed on circumference of a circle) may be specially designed for delivering the sustained drug delivery compositions for ophthalmic or acne and other medical application. Each needle may be able to dispense 0.01 ml or less volume of injectable compositions comprising drugs, preferably ophthalmic drugs in the cornea tissue surface or skin surface simultaneously. The compositions may be deposited at a depth of 10 to 300 microns in cornea or skin. Upon deposition, the injected composition will release the ophthalmic drug in the cornea for treating conditions such as bacterial infection, pain, inflammation, glaucoma, age-related macular degeneration and the like. Circular shape mentioned above is for example only. Other shapes such a single line, two crossed lines like and the like may also be used”[0249]. The instant specification defines “By way of example, keratoconus is a degenerative disorder that results in a weakening of the collagen in the eye, which ultimately leads to progressive distortions in the shape of the eye ball”[0005]. Thus the method of treating Keratoconus helps to teach claim 18.
This helps to teach claims 17-20.
The reference PATHAK does not teach wherein the buffer maintains the pH in the range of 6-8.5 for at least 15 minutes (claims 1-6 or 8, 10-11, 16-20, 21-23) or the buffer concentration of claim 6 or the time ranges in claim 9.
The Kumar teaches “The pH and buffering of an ophthalmic solution is probably equal importance to proper preservation. The stability of most commonly used ophthalmic solutions is largely controlled by the pH of their environment. The stability of nearly all products can be enhanced by refrigeration. Except for those few in which a decrease in solubility and precipitation might occur. In addition to stability effect, pH adjustment can influence comfort, safety, and activity of the product. Ideally, would be buffered to a pH of 7.4, considered the normal physiological pH of tear fluid. The pH values of ophthalmic solutions are adjusted within the range to provide an acceptable shelf life. They are buffered adequately to maintain stability within the range for at least 2 years… The buffer capacity is determined by buffer concentration” (page 4) and says that tolerable cornea ranges should be between pH 6.6 and 8.5(page 5).
This helps to teach claims 1-6 or 8, 10-11, 16-20, 21-23.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified PATHAK with Kumar because PATHAK teaches a composition that is meant to be applied to the eye with preferred effective conditions of application being pH 6-8, preferably pH 7.2 in biocompatible buffer like PBS, exposure time 1 minute to 12 h, preferably 30 minutes to 6 h and Kumar teaches that eye compositions should have a stable buffered pH around 7 and should maintain stability for an acceptable shelf life. Kumar also teaches that buffering capacity is determined by buffer concentration. Thus one of ordinary skill in the art would be motivated to improve the stability of the pH by routine optimization of buffer concentration for at least the duration of the exposure time preferably 30 minutes to 6 h if not in addition for an ideal shelf life. One would have a reasonable expectation of success to increase the buffer concentration to stabilize the pH for this desired exposure time because it is common practice in the art as taught by Kumar to increase buffer concentration to increase buffer capacity. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over PATHAK (PATHAK et al., US 20140271897 A1, 2014-09-18, IDS) as evidenced by PubChem (PubChem, Bis(sulfosuccinimidyl) suberate, 2005-08-08) in view of Kumar (Kumar et al., Recent Challenges and Advances in Ophthalmic Drug Delivery System, THE PHARMA INNOVATION, Vol. 1 No. 4 2012) further in view of Popiela (Popiela et al., Corneal Calcification and Phosphates: Do You Need to Prescribe Phosphate Free?, JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, Volume 30, Number 10, 2014) as evidenced by BENCH CHEM (BENCH CHEM. A Comprehensive Technical Guide on the pKa of Carbonic Acid: The Conjugate Acid of Potassium Carbonate, April 2026).
The references PATHAK and Kumar have been discussed supra and do not disclose carbonate-bicarbonate buffer(claim 7).
The reference Popiela teaches “ PHOSPHATE-BASED EXCIPIENTS used in ophthalmic preparations have been implicated in causing corneal calcification. In December 2012, after reviewing emerging evidence, the European Medicines Agency (EMA) confirmed this association and concluded that both patients and prescribers should be aware of this potential side effect” (page 800) and “Buffers exist in ophthalmic preparations to maintain a constant pH to prevent decomposition of active drugs and control tonicity. Various buffers (other than phosphate based) are used in ophthalmic solutions: acetic, boric, and hydrochloric acids, potassium and sodium bicarbonate, potassium and sodium borate, and citrate-based preparations. Phosphate buffers in drops occur at higher concentrations than the physiological concentration in the tear fluid. It has been estimated that it would require 20.4 days to form total corneal calcifications between the calcium in tears and unlimited phosphate”(801). The BENCH CHEM reference provides evidence that a bicarbonate buffer is a buffer system made up of carbonic acid (H₂CO₃), bicarbonate and carbonate ions (page 2). This helps to teach claim 7.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified PATHAK and Kumar with Popiela because PATHAK and Kumar both teach buffer systems for the eye and Popiela teaches alternative buffer systems for the eye. One of ordinary skill in the art would be motivated to substitute bicarbonate for phosphate because the phosphates used in ophthalmic preparations have been implicated in causing corneal calcification. One would have a reasonable expectation of success because bicarbonate buffer have been used before in ophthalmic solutions.
Conclusion
Claims 1-11 and 16-23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR HASTINGS whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627
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