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 .
Detailed Action
This office action is a response to applicant’s communication submitted July 15, 2026, wherein claims 41 and 42 are amended. This application is a national stage application of PCT/IB2021/000389, filed June 11, 2021, which claims benefit of provisional applications 63/056081, filed July 24, 2020, and 63/038361, filed June 12, 2020.
Claims 41-43, 45-48, 56, and 59-66 are pending in this application.
Claims 41-43, 45-48, 56, and 59-66 as amended are examined on the merits herein.
The following rejection of record in the previous action are maintained:
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.
Claims 41-43, 45-48, 56, 59-60, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Muller-Lierheim et al. (PCT international publication WO2018/069763, Reference of record in previous action) in view of Bikbova et al. (Reference of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 41 claims a method for treating nerve damage or loss in a human or animal comprising topically administering to the eye of the subject a high molecular weight hyaluronic acid having an intrinsic viscosity of at least 2.5 m3/kg.
Muller-Lierheim et al. discloses a method of establishing, restoring, and preserving the homeostasis or an ocular surface, comprising administering high molecular weight hyaluronic acid to the ocular surface, having a viscosity of greater than 2.5 m3/kg or 2.9 m3/kg. (p. 2 lines 16-21) The treatment reduces irritation, discomfort, inflammation, and immune response at the ocular surface. (p. 3 lines 11-14) Causes of disruptions to the homeostasis of the ocular surface can include trauma, microbial infection, or allergens. (p. 6 lines 8-12) In particular the conditions can be viral keratoconjunctivitis. (p. 7 lines 1-6) The subject can additionally have aqueous tear deficiency, or dry eye syndrome. (p. 10 lines 7-22) Regarding claims 44-48, p. 5 lines 29-31 of Muller-Lierheim discloses a step of identifying the subject as having the conditions prior to being treated.
While Muller-Lierheim does not specifically disclose that the method treats nerve damage or loss, Bikbova et al. discloses that diabetic keratopathy is an ocular complication of diabetes. (p. 294 right column third paragraph) Alterations of the tear film in diabetic eyes result in ocular discomfort, burning, and foreign body sensation. (p. 295 right column fourth paragraph) Corneas of diabetic patients displayed a decrease in long nerve fiber bundles. (p. 296 right column third paragraph) The clinical ocular findings in diabetic patients are related to those of dry eye patients and include reduced tear secretion and tear quality. (p. 297 right column second paragraph) Diabetic neurotrophic keratopathy is another ocular consequence of diabetic polyneuropathy. (p. 297 right column last two paragraphs) Muller-Lierheim further discloses that the use of artificial tears and lubricants to protect the ocular surface is a standard treatment for diabetic patients. (p. 298 right column fourth and fifth paragraphs)
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to administer the high molecular weight hyaluronic acid composition described by Muller-Lierheim et al. to a subject suffering from or at risk for diabetic keratopathy to reduce, limit, or treat the consequences of this disease. One of ordinary skill in the art would have found this to be suggested by the prior art in view of the fact that Bikbova discloses the use of protective ophthalmic compositions such as those described by Muller-Lierheim to treat this subset of patients.
Muller-Lierheim in view of Bikbova does not disclose a method comprising observing nerve damage or loss, for example by confocal microscopy.
Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph)
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM as a diagnostic tool in the diagnosis and monitoring of patients suffering from neurotrophic keratopathy associated with diabetes and peripheral diabetic neuropathy. One of ordinary skill in the art at the time of the invention would have seen the disclosure of Villani as suggesting this because Villani specifically describes using this method to monitor neurotrophic keratopathy, including that caused by diabetes.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 41-43, 45-48, 56, 59-60, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Muller-Lierheim et al. (PCT international publication WO2018/069763, Reference of record in previous action) in view of Bikbova et al. (Reference of record in previous action) in view of Di et al. (Reference of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 41 claims a method for treating nerve damage or loss in a human or animal comprising topically administering to the eye of the subject a high molecular weight hyaluronic acid having an intrinsic viscosity of at least 2.5 m3/kg.
Muller-Lierheim et al. discloses a method of establishing, restoring, and preserving the homeostasis or an ocular surface, comprising administering high molecular weight hyaluronic acid to the ocular surface, having a viscosity of greater than 2.5 m3/kg or 2.9 m3/kg. (p. 2 lines 16-21) The treatment reduces irritation, discomfort, inflammation, and immune response at the ocular surface. (p. 3 lines 11-14) Causes of disruptions to the homeostasis of the ocular surface can include trauma, microbial infection, or allergens. (p. 6 lines 8-12) In particular the conditions can be viral keratoconjunctivitis. (p. 7 lines 1-6) The subject can additionally have aqueous tear deficiency, or dry eye syndrome. (p. 10 lines 7-22) Regarding claims 44-48, p. 5 lines 29-31 of Muller-Lierheim discloses a step of identifying the subject as having the conditions prior to being treated.
While Muller-Lierheim does not specifically disclose that the method treats nerve damage or loss, Bikbova et al. discloses that diabetic keratopathy is an ocular complication of diabetes. (p. 294 right column third paragraph) Alterations of the tear film in diabetic eyes result in ocular discomfort, burning, and foreign body sensation. (p. 295 right column fourth paragraph) Corneas of diabetic patients displayed a decrease in long nerve fiber bundles. (p. 296 right column third paragraph) The clinical ocular findings in diabetic patients are related to those of dry eye patients and include reduced tear secretion and tear quality. (p. 297 right column second paragraph) Diabetic neurotrophic keratopathy is another ocular consequence of diabetic polyneuropathy. (p. 297 right column last two paragraphs) Muller-Lierheim further discloses that the use of artificial tears and lubricants to protect the ocular surface is a standard treatment for diabetic patients. (p. 298 right column fourth and fifth paragraphs)
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to administer the high molecular weight hyaluronic acid composition described by Muller-Lierheim et al. to a subject suffering from or at risk for diabetic keratopathy to reduce, limit, or treat the consequences of this disease. One of ordinary skill in the art would have found this to be suggested by the prior art in view of the fact that Bikbova discloses the use of protective ophthalmic compositions such as those described by Muller-Lierheim to treat this subset of patients.
Furthermore even assuming for the sake of argument that it is determined that Muller-Lierheim in view of Bibkova does not specifically suggest a method that would necessarily result in the claimed therapeutic benefit, the claimed invention would still have been obvious further in view of Di et al. Specifically, Di et al. discloses a study of the effect of 0.1% or 0.3% hyaluronic acid eye drops on corneal epithelial healing in diabetic mice. Administration of HA was seen to promote corneal nerve regeneration in diabetic mice after wounding of the cornea. (p. 1135 right column last paragraph, also figure 2) It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to administer the eye drops described by Muller-Lierheim et al. to a subject suffering from diabetic keratopathy with nerve damage, for the purpose of producing nerve regeneration and corneal axon outgrowth. One of ordinary skill in the art would have seen the disclosure of Di et al. as indicating that there is a reasonable expectation of success in achieving this therapeutic outcome using this therapeutic agent.
Muller-Lierheim in view of Bikbova does not disclose a method comprising observing nerve damage or loss, for example by confocal microscopy.
Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph)
It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM as a diagnostic tool in the diagnosis and monitoring of patients suffering from neurotrophic keratopathy associated with diabetes and peripheral diabetic neuropathy. One of ordinary skill in the art at the time of the invention would have seen the disclosure of Villani as suggesting this because Villani specifically describes using this method to monitor neurotrophic keratopathy, including that caused by diabetes.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 41-43, 46-48, 56, and 59-65 are rejected under 35 U.S.C. 103 as being unpatentable over Muller-Lierheim et al. (PCT international publication WO2018/069763, Reference of record in previous action) in view of Romano et al. (Reference of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 41 claims a method for treating nerve damage or loss in a human or animal comprising topically administering to the eye of the subject a high molecular weight hyaluronic acid having an intrinsic viscosity of at least 2.5 m3/kg.
Muller-Lierheim et al. discloses a method of establishing, restoring, and preserving the homeostasis or an ocular surface, comprising administering high molecular weight hyaluronic acid to the ocular surface, having a viscosity of greater than 2.5 m3/kg or 2.9 m3/kg. (p. 2 lines 16-21) The treatment reduces irritation, discomfort, inflammation, and immune response at the ocular surface. (p. 3 lines 11-14) Causes of disruptions to the homeostasis of the ocular surface can include trauma, microbial infection, or allergens. (p. 6 lines 8-12) In particular the conditions can be viral keratoconjunctivitis. (p. 7 lines 1-6) The subject can additionally have aqueous tear deficiency, or dry eye syndrome. (p. 10 lines 7-22) Regarding claims 44-48, p. 5 lines 29-31 of Muller-Lierheim discloses a step of identifying the subject as having the conditions prior to being treated.
Muller-Lierheim et al. does not disclose a method of treating a subject suffering from nerve damage or for achieving the therapeutic endpoints recited in the claims. However, Muller-Lierheim does disclose that additional active agents can be included in the eye drops. (p. 7 line 28 – p. 8 line 16) Romano et al. discloses that corneal innervation can be disrupted by various conditions including trauma, surgery, diabetes, long-term contact lens wear, and Sjögren’s syndrome. (p. 110 left column second paragraph) Romano et al. further describes a study of using eye drops containing HA, vitamin B12, and taurine as a treatment to promote nerve regeneration. (p. 110 left column fourth paragraph) These eye drops were seen to promote corneal nerve regeneration. (pp. 114-115 section 3.4. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to include taurine and vitamin B12 in the eyedrops described by Muller-Lierheim et al. so as to promote nerve regeneration in subjects suffering from ocular conditions with nerve damage. One of ordinary skill in the art would specifically have seen the disclosure of Romano as suggesting that modifying these prior art eye drops by adding taurine and vitamin B12 and use the resulting product to promote nerve regeneration in patients suffering from corneal nerve damage. One of ordinary skill in the art would have seen the disclosure of Romano as suggesting that HA eye drops having these ingredients would be useful for achieving this therapeutic endpoint in this subject population.
Muller-Lierheim in view of Romano does not disclose a method comprising observing nerve damage or loss, for example by confocal microscopy.
Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM to identify subjects who suffer from loss of corneal innervation and could benefit from a treatment aimed at restoring corneal innervation.
Regarding claim 60, a composition having the same characteristics recited in claim 60 is disclosed as a preferred therapeutic agent in the method described by Muller-Lierheim.
Regarding claims 61-65, Muller-Lierheim et al. discloses that the disruption to ocular homeostasis can include surgery, contact lens wearing, and microbial infection, for example. (p. 6 lines 8-12) Medical therapies include small molecule pharmaceuticals (medicamentosa) that can cause the condition, (p. 6 lines 13-15) or viral keratoconjunctivitis. (p. 7 line 2) Additionally Romano discloses that disruptions to corneal nerves can be caused by surgery, trauma, microbial infection, and diabetes. (p. 110 left column second paragraph) In view of these disclosures it would have been obvious to one of ordinary skill in the art at the time of the invention to administer the aforementioned ophthalmic composition to subjects suffering from disruptions to corneal innervations due to any of these causes. One of ordinary skill in the art would have seen these references as suggesting that all of these patient populations can suffer from disrupted corneal innervation and neurotrophic keratopathy which can be treated in this manner.
For these reasons the invention taken as a whole is prima facie obvious.
Claims 62 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Muller-Lierheim et al. in view of Romano et al. in view of Villani et al. as applied to claims 41-43, 46-48, 56, and 59-65 above, and further in view of Versura et al. (Reference of record in previous action)
The disclosures of Muller-Lierheim et al., Romano et al., and Villani et al. are discussed above. Muller-Lierheim et al. in view of Romano et al. in view of Villani et al. does not specifically describe treating a disorder of corneal innervation which is caused by medicamentosa (medicament use) or multiple sclerosis.
Versura et al. discloses that neurotrophic keratitis can be caused by various conditions that impair innervation, including herpes simplex or herpes zoster infections, corneal surgery, use of topical mediations, diabetes, and multiple sclerosis. (p. 38 right column third – seventh paragraphs) It would have been obvious to one of ordinary skill in the art at the time of the invention to administer the ophthalmic compositions described by Muller-Lierheim in view of Romano to these groups of patients. One of ordinary skill in the art would have seen the prior art as providing a reasonable expectation that topical ophthalmic treatment with these compositions would have the desired effect of promoting nerve regeneration and restoring corneal innervation in these subjects.
For these reasons the invention taken as a whole is prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 41-43, 46-48, 56, and 59-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, and 7-9 of U.S. Patent No. 12303527 (of record in previous action, herein referred to as ‘527) in view of Romano et al. (of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 1 of ‘527 claims a method of treating severe ocular surface disease in a patient suffering therefore comprising administering a fluid containing high molecular weight hyaluronic acid having a viscosity of greater than 2.5 m3/kg to the eye of a subject. Dependent claim 2 of ‘527 describes the condition as severe dry eye, which would necessarily involve decreased tearing rate, abnormal tear production or dryness, and tear film deficiency as recited in present claims 47, 48, and 54. Claims 5 and 7 of ‘527 further describe the hyaluronic acid fluid as having the same characteristics recited in present claims 59 and 60. While the claims of ‘529 do not specify that the patient suffers from nerve damage or loss in the cornea of the eye, and that treatment results in the claimed therapeutic outcome, Romano et al. discloses that corneal innervation can be disrupted by various conditions including trauma, surgery, diabetes, and Sjögren’s syndrome. (p. 110 left column second paragraph) Romano et al. further describes a study of using eye drops containing HA, vitamin B12, and taurine as a treatment to promote nerve regeneration. (p. 110 left column fourth paragraph) These eye drops were seen to promote corneal nerve regeneration. (pp. 114-115 section 3.4. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to include taurine and vitamin B12 in the eyedrops described in the claims of ‘527 so as to promote nerve regeneration in subjects suffering from ocular conditions with nerve damage. One of ordinary skill in the art would specifically have seen the disclosure of Romano as suggesting that modifying these prior art eye drops by adding taurine and vitamin B12 and use the resulting product to promote nerve regeneration in patients suffering from corneal nerve damage. One of ordinary skill in the art would have seen the disclosure of Romano as suggesting that HA eye drops having these ingredients would be useful for achieving this therapeutic endpoint in this subject population.
Regarding the newly added step of identifying the subject as having corneal nerve damage or loss, Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM to identify subjects who suffer from loss of corneal innervation and could benefit from a treatment aimed at restoring corneal innervation.
Claims 41-43, 46-48, 56, and 59-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 96, 111, 112, 114, and 118 of copending Application No. 16/341915 (US pre-grant publication 2019/0240251, of record in previous action, herein referred to as ‘915) in view of Romano et al. (Reference of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 96 of ‘915 claims a method of treating severe dry eye in a patient suffering therefore comprising administering a fluid containing high molecular weight hyaluronic acid having a viscosity of greater than 2.9 m3/kg to the eye of a subject. Severe dry eye would necessarily involve decreased tearing rate, abnormal tear production or dryness, and tear film deficiency as recited in present claims 47, 48, and 54. Claims 111, 112, and 114 of ‘915 further describe the hyaluronic acid fluid as having the same characteristics recited in present claim 60. While the claims of ‘915 do not specify that the patient suffers from nerve damage or loss in the cornea of the eye, and that treatment results in the claimed therapeutic outcome, Romano et al. discloses that corneal innervation can be disrupted by various conditions including trauma, surgery, diabetes, and Sjögren’s syndrome. (p. 110 left column second paragraph) Romano et al. further describes a study of using eye drops containing HA, vitamin B12, and taurine as a treatment to promote nerve regeneration. (p. 110 left column fourth paragraph) These eye drops were seen to promote corneal nerve regeneration. (pp. 114-115 section 3.4. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to include taurine and vitamin B12 in the eyedrops described in the claims of ‘915 so as to promote nerve regeneration in subjects suffering from ocular conditions with nerve damage. One of ordinary skill in the art would specifically have seen the disclosure of Romano as suggesting that modifying these prior art eye drops by adding taurine and vitamin B12 and use the resulting product to promote nerve regeneration in patients suffering from corneal nerve damage. One of ordinary skill in the art would have seen the disclosure of Romano as suggesting that HA eye drops having these ingredients would be useful for achieving this therapeutic endpoint in this subject population.
Regarding the newly added step of identifying the subject as having corneal nerve damage or loss, Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM to identify subjects who suffer from loss of corneal innervation and could benefit from a treatment aimed at restoring corneal innervation.
This is a provisional nonstatutory double patenting rejection.
Claims 41-43, 46-48, 56, and 59-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37, 41, and 44 of copending Application No. 18/002673 (US pre-grant publication 2023/0338541, cited in PTO-1449, herein referred to as ‘673) in view of Romano et al. (Reference of record in previous action) in view of Villani et al. (Reference of record in previous action)
Independent claim 37 of ‘673 claims a method of treating an eye disorder in a human or non-human subject comprising administering a fluid containing high molecular weight hyaluronic acid having a viscosity of greater than 2.5 m3/kg to the eye of a subject. Dependent claims 41 and 42 of ‘673 further describe the ocular disorder as selected from a list including glaucoma and ocular surface disorder, for example. While the claims of ‘673 do not specify that the patient suffers from nerve damage or loss in the cornea of the eye, and that treatment results in the claimed therapeutic outcome, Romano et al. discloses that corneal innervation can be disrupted by various conditions including trauma, surgery, diabetes, and Sjögren’s syndrome. (p. 110 left column second paragraph) Romano et al. further describes a study of using eye drops containing HA, vitamin B12, and taurine as a treatment to promote nerve regeneration. (p. 110 left column fourth paragraph) These eye drops were seen to promote corneal nerve regeneration. (pp. 114-115 section 3.4. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to include taurine and vitamin B12 in the eyedrops described in the claims of ‘673 so as to promote nerve regeneration in subjects suffering from ocular conditions with nerve damage. One of ordinary skill in the art would specifically have seen the disclosure of Romano as suggesting that modifying these prior art eye drops by adding taurine and vitamin B12 and use the resulting product to promote nerve regeneration in patients suffering from corneal nerve damage. One of ordinary skill in the art would have seen the disclosure of Romano as suggesting that HA eye drops having these ingredients would be useful for achieving this therapeutic endpoint in this subject population.
Regarding the newly added step of identifying the subject as having corneal nerve damage or loss, Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM to identify subjects who suffer from loss of corneal innervation and could benefit from a treatment aimed at restoring corneal innervation.
This is a provisional nonstatutory double patenting rejection.
Claims 41-43, 46-48, 56, and 59-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, and 8 of copending Application No. 19/211590 (US pre-grant publication 2025/0276004, of record in previous action in view of Villani et al. (Reference of record in previous action)n, herein referred to as ‘590) in view of Romano et al. (Reference of record in previous action)
Independent claim 1 of ‘590 claims a method of treating severe ocular surface disease, including severe dry eye in a patient suffering therefore comprising administering a fluid containing high molecular weight hyaluronic acid having a viscosity of greater than 2.5 m3/kg to the eye of a subject. Dependent claim 2 of ‘590 describes the condition as severe dry eye, which would necessarily involve decreased tearing rate, abnormal tear production or dryness, and tear film deficiency as recited in present claims 47, 48, and 54. Claims 6 and 8 of ‘590 further describe the hyaluronic acid fluid as having the same characteristics recited in present claims 59 and 60. While the claims of ‘590 do not specify that the patient suffers from nerve damage or loss in the cornea of the eye, and that treatment results in the claimed therapeutic outcome, Romano et al. discloses that corneal innervation can be disrupted by various conditions including trauma, surgery, diabetes, and Sjögren’s syndrome. (p. 110 left column second paragraph) Romano et al. further describes a study of using eye drops containing HA, vitamin B12, and taurine as a treatment to promote nerve regeneration. (p. 110 left column fourth paragraph) These eye drops were seen to promote corneal nerve regeneration. (pp. 114-115 section 3.4. It would therefore have been obvious to one of ordinary skill in the art at the time of the invention to include taurine and vitamin B12 in the eyedrops described in the claims of ‘590 so as to promote nerve regeneration in subjects suffering from ocular conditions with nerve damage. One of ordinary skill in the art would specifically have seen the disclosure of Romano as suggesting that modifying these prior art eye drops by adding taurine and vitamin B12 and use the resulting product to promote nerve regeneration in patients suffering from corneal nerve damage. One of ordinary skill in the art would have seen the disclosure of Romano as suggesting that HA eye drops having these ingredients would be useful for achieving this therapeutic endpoint in this subject population.
Regarding the newly added step of identifying the subject as having corneal nerve damage or loss, Villani et al. discloses that In vivo confocal microscopy (IVCM) is used to observe alterations of ocular surface microstructure in both clinical and laboratory settings. (p. 214 left column first paragraph) In particular, IVCM is described as being useful for monitoring the state of nerve regeneration in patients suffering from neurotrophic keratopathy from conditions including diabetes mellitus and herpes zoster ophthalmicus. (p. 220 right column third paragraph) Villani also specifically describes IVCM as useful for diagnosing peripheral neuropathy, such as diabetic neuropathy. (p. 220 right column last paragraph – p. 221 left column second paragraph) It would have been obvious to one of ordinary skill in the art at the time of the invention to use IVCM to identify subjects who suffer from loss of corneal innervation and could benefit from a treatment aimed at restoring corneal innervation.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments, submitted July 15, 2026, with respect to the above grounds of rejection, have been fully considered and not found to be persuasive to remove the rejection.
With respect to the rejection of claims 41-43, 45-48, 56, 59-60, and 65 under 35 USC 103 for being obvious over Muller-Lierheim et al. ‘763 in view of Bibkova et al. in view of Villani et al., Applicant argues that ‘763 does not disclose treating nerve damage or loss, and also does not disclose treating diabetes or related ocular conditions. Applicant further argues that Bibkova et al. does not specifically disclose using hyaluronic acid as a treatment for diabetic ocular disease, but rather generally describes using artificial tears and lubricants to protect the ocular surface. On this basis, Applicant argues that there is no connection between the diseases described by ‘763, and the diabetic conditions described by Bibkova.
However, looking to the disclosures of Bibkova and ‘763, the specific functions of high molecular weight HA described by ‘763 are the same as the function of protecting the ocular surface described by Bibkova as a treatment for diabetic ocular surface disease. This is the connection between the disclosures of ‘763 and Bibkova. As described in MPEP 2144(IV), “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant.” In the present case, a patient suffering from diabetic ocular disease would be a patient “having corneal nerve damage or corneal nerve loss” as recited in present claim 41, and would further be in need of treatment to protect the ocular surface, for example HMW HA as described by ‘763. This is the rationale by which one of ordinary skill in the art would arrive at a motivation to administer HMW HA to a subject falling within the claimed subject population. While the prior art does not specifically suggest that HMW HA has a direct effect on nerve cells, it does suggest applying the same therapeutic agent to the same subject population as recited in the claims, in such a way that it is reasonable to expect that it would teach the same therapeutic outcome. Applicant has not identified any manner in which the claimed method objectively differs from a method of administering the same composition not the same subject as a lubricating agent to protect the ocular surface. For these reasons the rejection is deemed proper and maintained.
With respect to the rejection over the above references further in view of Di, Applicant argues that the nerve injury treatment model described by Di differs from the claimed invention. Specifically, Applicant argues that the treatment described by Di involves pre-treatment with HA, which is different from using HA to treat existing injury. Firstly, while the experimental protocol used by Di involves pretreatment, administration of HA in continued after injury. (see p. 1134 left column fourth paragraph) Therefore it is not the case that the protocol described by Di does not involve administering HA to a subject having an existing wound. This is especially relevant in the case of diabetic patients, since diabetic keratopathy is a progressive disease, and treatment over an extended period of time, including pre-treatment of patients at risk of corneal nerve loss due to diabetic ocular disease, would be a reasonable therapeutic approach.
With respect to the rejection of claims 41-43, 46-48, 56, and 59-65 as obvious over Muller-Lierheim in view of Romano in view of Villani, and of claims 62 and 66 over the same references further in view of Versura, Applicant argues that Romano discloses that the therapeutic effect observed by Romano was due to eye drops comprising vitamin B12 in addition to HA, and that no effect was observed for eye drops containing only HA. However, as presently written the claims refer to administering a fluid “comprising” high molecular weight HA. Therefore the claims are infringed by therapeutic methods in which the HA is only one of multiple therapeutic ingredients in the composition, so long as the prior art suggests including it in the composition along with other compounds such as vitamin B12.
With respect to the rejections on the grounds of double patenting, Applicant makes no further arguments specifically touching the merits of these rejections.
For these reasons all rejections of record in the previous action are maintained.
Conclusion
No claims are allowed in this action. 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.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 8/25/2026
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