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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
No IDS is currently on file.
Claim Status
Claims 1-21, filed 9/8/2023, are pending. Claims 1-21 are under examination.
Claim Objections
Claim 1 is objected to because of the following informalities. Claim 1 recites the phrase “… and 0.5-100 mM phosphate buffer, PB.” It would be more consistent to denote “PB” as an abbreviation with parentheses: “(PB)”. Appropriate correction is required.
Claims 8 and 16-21 are objected to because of the following informalities. The phrase “comprising temperature sensitive gel eye drops and a temperature sensitive gel external spray” is better written as ““further comprising temperature sensitive gel eye drops and a temperature sensitive gel external spray”. Appropriate correction is required.
Claim Interpretation
Claims 1-7 will be interpreted as referring to human serum albumin and any epidermal growth factor. No sequence information is provided, however the specification references human epidermal growth factor at para. [0006]: ” Human Epidermal Growth Factor (hEGF) is a biologically active protein composed of 53 amino acids secreted by the human body, is widely distributed in body fluids such as blood, saliva, and urine, has a wide range of biological activities, and promotes the division of epidermal cells, accelerates cellular metabolism, and allows new epidermal cells to rapidly replace aged cells.”
The specification then references EGF at para. [0007]: ” In view of this, the present disclosure aims to provide a temperature sensitive gel damage repair formulation and an application thereof. The formulation can not only preserve the biological activity of recombinant human serum albumin/epidermal growth factor fusion protein (rHSA/EGF) well, but also form a gel at a drug application site so as to remain at the drug application site for a longer period of time, and make slow release of active fusion protein in the formulation easier so as to achieve a longer half-life, thereby improving the treatment effect of the formulation.”
From this, it appears hEGF refers to human epidermal growth factor and EFG refers to epidermal growth factor in general.
Regarding claim 1, “PB” will be interpreted as meaning “phosphate buffer” and intended as an abbreviation.
Regarding claim 8, claim 8 will be interpreted as the temperature sensitive gel repair formulation according to claim 1, in the form of gel eye drops or a gel external spray.
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 8-21 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 claim 8, claim 8 recites “… comprising temperature sensitive gel eye drops and a temperature sensitive gel external spray.” Para. [0025] of the specification states: “FIG. 2 shows that recombinant human serum albumin/epidermal growth factor fusion protein temperature sensitive gel eye drops and recombinant human serum albumin/epidermal growth factor fusion protein eye drops (spray) are simultaneously applied to healthy volunteers, …”. This passage strongly implies that the composition of claim 1 is in the form of gel eye drops or a gel external spray, but these elements are not actually part of the composition. Furthermore it is not clear how the gel could be in the form of drops and a spray at the same time.
Consequently, claim 1 does not further comprise these elements rendering the scope of claim 8 unclear. Claim 8 is rejected.
Regarding claims 9-15, these claims all follow the format “An application of the temperature sensitive gel damage repair formulation according to claim 1 for…”. These claims are in the form of method claims but lack any positively recited steps for a person of ordinary skill in the art to actually perform. Consequently, they are indefinite and rejected.
Regarding claims 16-21, these claims all follow the format of claim 8 above: “… comprising temperature sensitive gel eye drops and a temperature sensitive gel external spray.”
Para. [0025] of the specification states: “FIG. 2 shows that recombinant human serum albumin/epidermal growth factor fusion protein temperature sensitive gel eye drops and recombinant human serum albumin/epidermal growth factor fusion protein eye drops (spray) are simultaneously applied to healthy volunteers, …” This passage strongly implies that the composition of claim 1 is in the form of gel eye drops or a gel external spray, but these elements are not actually part of the composition.
Consequently, claim 1 does not further comprise these elements rendering the scope of claims 16-21 unclear. Claims 16-21 are rejected.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating cornea damage as a result of keratitis, does not reasonably provide enablement for preventing or treating keratitis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
Claim 10 is an application of the temperature sensitive gel repair formulation of claim 1. Claim 1 is fairly specific, as is the disease keratitis. The scope of treating and/or preventing, however is quite broad.
The nature of the invention;
The invention is an application of the temperature sensitive gel repair formulation of claim 1.
The state of the prior art;
Austin et al. (Austin, et al. Ophthalmology 124.11: 1678-1689. (2017)) discloses that “Corneal disease remains the leading cause of monocular blindness worldwide, especially affecting marginalized populations. Corneal opacities, which are largely caused by infectious keratitis, are the fourth leading cause of blindness globally and are responsible for 10% of avoidable visual impairment in the world's least developed countries.” (Austin et al., page 1678, col. 1, para. 1). Therefore, keratitis causes corneal damage.
Austin further elucidates that keratitis can be caused by bacteria, fungus, or viruses (Austin et al, pages 1682 and 1684, Tables 1 and 2).
The level of one of ordinary skill;
A person of ordinary skill in the art typically would possess at least a Master’s level education and frequently a Ph.D.
The level of predictability in the art;
As described by Austin, the causes of keratitis are well-understood. Many treatments are also disclosed by Austin as described above. A person of ordinary skill in the art would predict that an antibiotic, for example, well have a reasonable chance of treating bacterial keratitis, but not viral keratitis.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant discloses corneal repair results using the composition of claim 1. Applicant does not disclose any treatment or prevention data for keratitis itself.
Regarding claim 10, claim 10 recites an application of the temperature sensitive gel damage repair formulation according to claim 1 in preparing a drug for preventing and/or treating keratitis. As discussed above, Applicant only shows data concerning repair/healing of corneal epithelium tissue. It would require undue experimentation for a person of ordinary skill in the art to determine if the composition of claim 1 can treat and/or prevent keratitis.
Consequently, the specification does not enable any person skilled in the art to use the invention commensurate in scope with these claims and claim 10 is rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-8 and 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Kim, et al. International journal of pharmaceutics 233.1-2:159-167. (2002)) in view of Akkari et al. (Akkari, et al Materials Science and Engineering: C 68: 299-307 (2016)), Sleep (Sleep, Darrell. Expert opinion on drug delivery 12.5: 793-812 (2015)), Higuchi et al. (Higuchi, et al. Current eye research 32.2: 83-88 (2007)), Pavani et al. (Pavani, et al. Journal of Molecular Liquids 331: 115753 (2021)), Platts et al. (Platts, e al. International Journal of Pharmaceutics 486.1-2: 131-135 (2015)) and Rusciano et al. (Rusciano, et al. European journal of pharmacology 787: 9-19 (2016)).
Regarding claim 1, claim 1 recites a temperature sensitive gel damage repair formulation, comprising components at the following concentrations: 0.01-5 mg/mL recombinant human serum albumin/epidermal growth factor fusion protein, 1.9-2.6% m/m glycine, 3.9-6.2% m/m poloxamer 188, 16.3-18.2% m/m poloxamer 407, and 0.5-100 mM phosphate buffer, PB.
Kim et al. discloses a temperature sensitive poloxamer gel that contains poloxamer 407, poloxamer 188, and human epithelial growth factor: “The purpose of the present study is to prepare chemically and physically stable rhEGF/poloxamer gel and to investigate its possibility of ophthalmic delivery. The rhEGF/HP-β-CD complex markedly increased rhEGF stability compared with rhEGF solution at 4 °C. The poloxamer gel was composed of poloxamer 407 (16%) and poloxamer 188 (14%). “ (Kim et al., page 159, Abstract). Kim also discloses that varying the poloxamer content of the gel modulates the gelation temperature. (Kim et al., page 164, Table 1).
Kim et al. does not specifically disclose a fusion protein of human serum albumin and human epithelial growth factor, glycine, or phosphate buffer.
However, Sleep et al. discloses the usage of albumin fusion proteins: “The advantage for the drug developer is a greatly simplified commercial manufacturing process with the albumin fusion being secreted fully folded into the fermentation broth from which it can be purified utilising albumin as a purification tag, facilitating the development of platform manufacturing processes.” (Sleep et al., page 800, col. 1, para. 3). Sleep also discloses that albumin is used to modulate the half life of attached molecules: “Albumin has an exceptionally long 19-day circulatory half-life due to a combination of reduced renal filtration and FcRn-mediated recycling. Consequently, various strategies have sought to extend the circulatory half-life of small molecules, peptides and proteins by engaging them covalently or transiently with albumin.” (Sleep et al., page 799, col. 1, para. 1)
Furthermore, Higuchi et al. discloses that human serum albumin has some therapeutic efficacy for the dry eye condition: “In this and previous studies from our group, we have shown that HSA has potential for clinical treatment of dry eye patients.” (Higuchi et al., page 86, col. 2, para. 2).
Regarding glycine, Platts et al. discloses that “Glycine is another commonly used amino acid in protein formulations and a well-known stabilizer.” (Platts, et al., page 131, col. 2, para. 1). Furthermore, Rusciano et al. discloses that glycine also adds therapeutic benefit for treatment of the inflammation associated with dry eye disorder: “Glycine, histidine and cysteine administered to human coronary arterial endothelial cells can each inhibit NF-kB activation, IL-6 production and expression of the leukocyte adhesion molecule CD62E (Hasegawa et al., 2012).” (Rusciano, et al., page 11, col. 2, para. 3). Rusciano discloses that glycine is used in topical eye treatments: “Given these results, topical eye drop formulations containing amino acids with or without hydrating agents (such as hyaluronic acid or hydroxy-propyl-methyl-cellulose) have been designed and are currently available on the market. Four amino acids have been chosen in the topical formulation: proline, lysine, leucine and glycine.) (Rusciano et al., page 12, col. 2, para. 3).
Regarding phosphate buffer, Pavani et al. discloses that phosphate buffers are frequently used in protein compositions: “In biological research and biochemical processes, PBS is one of promising used buffer solution. The phosphate buffer system is one of the acid-base buffer systems of extracellular fluids of organisms. The pair of H2PO−4/HPO4−2 is capable of buffering in a particular pH range. The concentration of phosphate ions in the body varies in different types of biological medium [21]. This buffer generally helps to maintain a constant pH around 7.0. PBS buffer not only regulates alternation in pH and also stabilizes the proteins Therefore, use of PBS buffer has been claimed to stabilize proteins for long term storage and biological experiments.” (Pavani et al., page 2, col. 1, para. 3).
Regarding the claimed concentrations, MPEP 2144.05(II)(A) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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).”
Furthermore, Akkari et al. discloses various PL407-PL188 ratios, including a PL407-PL188 ratio of 25:5% (Akkari et al., page 303, Table 3). Kim discloses other PL407-PL188 ratios such as 16:14%, 16:10%, and 20:20% that result in gelation at various temperatures. (Kim et al., page 164, Table 1). These two sets of disclosed ratios “bracket” the claimed ratios of 16.3-18.2:3.9-6.2% . Therefore, a person of ordinary skill in the art would be able to arrive at the claimed range via routine optimization.
The concentrations of fusion protein, glycine, and phosphate buffer are similarly determinable by a person of ordinary skill in the art through routine optimization.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the human epidermal growth factor and poloxamer gel of Kim with the human serum albumin of Sleep and Higuchi, the glycine of Platts and Rusciano, and the phosphate buffer of Pavani to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to create a fusion of human serum albumin and human epidermal growth factor because human epidermal growth factor can treat corneal epithelial tissue as disclosed by Kim: “Human epithelial growth factor (rhEGF) is a single-chain polypeptide containing 53 amino acid residues (MW=6045) and three disulfide bridges (Senderoff et al., 1994). rhEGF stimulates the proliferation and differentiation of epithelial tissues such as in the intestinal mucosa, corneal epithelial tissue, lung and trachea epithelial (Carpenter and Cohen, 1979). Moreover, rhEGF also inhibits gastric acid secretion (Bower et al., 1975, Elder et al., 1975, Gregory, 1975, Konturek et al., 1984).” (Kim et al., page 159, col. 1, para. 1).
Fusing the human epidermal growth factor to human serum albumin would increase the half and simplify manufacture as discussed above by Sleep as well as gain the additional therapeutic benefits disclosed by Higuchi above.
A person of ordinary skill in the art would be motivated to add glycine both as a protein stabilizer as discussed by Platts above and to gain the therapeutic benefit disclosed by Rusciano above.
A person of ordinary skill in the art would use phosphate buffer because phosphate buffer stabilizes proteins and buffers a useful pH range as discussed by Pavani above.
A person of ordinary skill in the art would have a reasonable expectation of success because both human epidermal growth factor and human serum albumin have therapeutic value for dry eyes as discussed above. MPEP 2144.06(I) states: “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).”
However, a person of ordinary skill in the art would also have a reasonable expectation of success because Sleep discloses that many therapeutics are known that are fusions of human serum albumin (Sleep et al., page 801, Table 2).
The composition disclosed by Kim includes a cyclodextrin, but this component is for stabilization of peptides: “Recently, cyclodextrin (CD) have been used to increase chemical and enzymatic stability of the peptides. CDs are groups of cyclic oligosaccharides which have been shown to improve physicochemical properties of many drugs through formation of inclusion complexes. Among the CDs, the β-CD and Hydroxy-β-cyclodextrin (HP-β-CD) exhibited the highest stabilizing effect for calcitonin and octreotide (Haeberlin et al., 1996). In particular, HP-β-CD is most commonly applied in aqueous eye drop formulations because of lower toxicity compared to parent CDs.” (Kim et al., page 160, col. 1, para. 1).
Regarding glycine, a person of ordinary skill in the art would have a reasonable expectation of success because Platts discloses that “Glycine is another commonly used amino acid in protein formulations and a well-known stabilizer.” (Platts, et al., page 131, col. 2, para. 1). Glycine is effectively a substitution of the cyclodextrin of Kim in terms of protein stabilization, but also provides therapeutic benefit as described by Rusciano above. In this way, glycine would reasonably be expected to perform better than cyclodextrin for this application.
Regarding phosphate, a person of ordinary skill in the art would have a reasonable expectation of success because Pavani discloses: ““In biological research and biochemical processes, PBS is one of promising used buffer solution. The phosphate buffer system is one of the acid-base buffer systems of extracellular fluids of organisms.” (Pavani et al., page 2, col. 1, para. 3).
Consequently, claim 1 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. Claim 2 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 1.
Consequently, claim 2 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 3, claim 2 is obvious as described above. Claim 3 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 2.
Consequently, claim 3 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 4, claim 1 is obvious as described above. Claim 4 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 1.
Consequently, claim 4 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 5, claim 1 is obvious as described above. Claim 5 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 1.
Consequently, claim 5 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 6, claim 1 is obvious as described above. Claim 6 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 1.
Consequently, claim 6 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 7, claim 6 is obvious as described above. Claim 6 further recites narrower concentration ranges which may be determined by a person of ordinary skill in the art through routine optimization as described in claim 6.
Consequently, claim 7 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 8, claim 1 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 8 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 16, claim 2 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 16 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 17, claim 3 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 17 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 18, claim 4 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 18 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 19, claim 5 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 19 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 20, claim 6 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 20 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Regarding claim 21, claim 7 is obvious as described above. Kim et al. discloses the delivery form of drops: “After ocular instillation, aqueous eye drop solution and suspension will mix with the tear fluid and be dispersed over the eye surface. The rapid loss of the instilled solution from the pre-corneal area will limit the ocular absorption. Therefore, prolonged corneal contact time of the applied drug is very important. The thermoreversible poloxamer gel system would be easy to administer with good patient compliance. It is also better retained in the eye than conventional eye drops avoiding rapid loss of the drug from the pre-corneal area.” (Kim et al., page 160, col. 1, para. 2).
Consequently, claim 21 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. and rejected.
Claims 9 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. Kim, et al. International journal of pharmaceutics 233.1-2:159-167. (2002)) in view of Akkari et al. (Akkari, et al Materials Science and Engineering: C 68: 299-307 (2016)), Sleep (Sleep, Darrell. Expert opinion on drug delivery 12.5: 793-812 (2015)), Higuchi et al. (Higuchi, et al. Current eye research 32.2: 83-88 (2007)), Pavani et al. (Pavani, et al. Journal of Molecular Liquids 331: 115753 (2021)), Platts et al. (Platts, e al. International Journal of Pharmaceutics 486.1-2: 131-135 (2015)) and Rusciano et al. (Rusciano, et al. European journal of pharmacology 787: 9-19 (2016)) as applied to claim 1 above, and further in view of Xiao, et al. (Xiao, et al. Investigative ophthalmology & visual science 53.1: 191-197 (2012)).
Regarding claim 9, claim 1 is obvious as described above. Claim 9 further recites an application of the temperature sensitive gel damage repair formulation according to claim 1 in preparing a drug for repairing cornea and/or conjunctiva damage.
Kim et al. discloses that human epidermal growth factor can help repair cornea damage: “Human epithelial growth factor (rhEGF) is a single-chain polypeptide containing 53 amino acid residues (MW=6045) and three disulfide bridges (Senderoff et al., 1994). rhEGF stimulates the proliferation and differentiation of epithelial tissues such as in the intestinal mucosa, corneal epithelial tissue, lung and trachea epithelial (Carpenter and Cohen, 1979). Moreover, rhEGF also inhibits gastric acid secretion (Bower et al., 1975, Elder et al., 1975, Gregory, 1975, Konturek et al., 1984).” (Kim et al., page 159, col. 1, para. 1).
Furthermore, Xiao et al. discloses that EGF is a known therapeutic for dry eye and corneal repair:
“Among numerous managements for dry eye, the first-line choice is topical application of artificial tears which has been proven to relieve symptoms of irritation and decrease corneal
dye staining in mild to moderate clinical conditions. However, the imperfect performance of artificial tears in severe cases may result from lack of active agents such as epidermal growth
factor (EGF), hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A. These essential components in the tear film play important roles in maintaining ocular surface health. Topical application of autologous serum (AS), which can supplement the active agents, leads to recovery in many severe dry eye cases.5–7 However, the relatively complicated preparation and safety concerns limit its use in individuals.
EGF is the key component of both tear film and serum. EGF is a potent polypeptide mitogen that belongs to the EGF family of growth factors. It has been demonstrated that EGF in the tear film is secreted by the lacrimal gland and plays a vital role in the corneal epithelium maintenance and wound healing.8–11 Symptoms of dry eye in patients with solid tumors treated with systemic therapy of EGF receptor (EGFR) inhibitor, led to the hypothesis that topical application of EGF may be a promising therapy for dry eye.12 However, the efficacy of EGF eye drops on dry eye has not been adequately discussed so far. The aim of this study was to investigate the therapeutic effects of EGF on the mouse dry eye models induced by topical administration of benzalkonium chloride (BAC)13,14 and the mechanisms underlying these effects.” (Xiao et al, page 191., col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the temperature sensitive gel damage repair formulation of Kim et al., Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. in a drug meant to repair cornea damage as described by Xiao.
MPEP 2144.06(I) states: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).”
A person of ordinary skill in the art would be motivated to prevent the negative outcomes described by Xiao: “Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.” (Xiao, et al., page 191, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success based on how Kim and Xiao describe EFG being able to improve corneal repair and corneal health above.
Consequently, claim 9 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Xiao et al. and rejected.
Regarding claim 13, claim 1 is obvious as described above. Claim 13 further recites an application of the temperature sensitive gel damage repair formulation according to claim 1 for repairing cornea and/or conjunctiva damage.
Kim et al. discloses that human epidermal growth factor can help repair cornea damage: “Human epithelial growth factor (rhEGF) is a single-chain polypeptide containing 53 amino acid residues (MW=6045) and three disulfide bridges (Senderoff et al., 1994). rhEGF stimulates the proliferation and differentiation of epithelial tissues such as in the intestinal mucosa, corneal epithelial tissue, lung and trachea epithelial (Carpenter and Cohen, 1979). Moreover, rhEGF also inhibits gastric acid secretion (Bower et al., 1975, Elder et al., 1975, Gregory, 1975, Konturek et al., 1984).” (Kim et al., page 159, col. 1, para. 1).
Furthermore, Xiao et al. discloses that EGF is a known therapeutic for dry eye and corneal repair:
“Among numerous managements for dry eye, the first-line choice is topical application of artificial tears which has been proven to relieve symptoms of irritation and decrease corneal
dye staining in mild to moderate clinical conditions. However, the imperfect performance of artificial tears in severe cases may result from lack of active agents such as epidermal growth
factor (EGF), hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A. These essential components in the tear film play important roles in maintaining ocular surface health. Topical application of autologous serum (AS), which can supplement the active agents, leads to recovery in many severe dry eye cases.5–7 However, the relatively complicated preparation and safety concerns limit its use in individuals.
EGF is the key component of both tear film and serum. EGF is a potent polypeptide mitogen that belongs to the EGF family of growth factors. It has been demonstrated that EGF in the tear film is secreted by the lacrimal gland and plays a vital role in the corneal epithelium maintenance and wound healing.8–11 Symptoms of dry eye in patients with solid tumors treated with systemic therapy of EGF receptor (EGFR) inhibitor, led to the hypothesis that topical application of EGF may be a promising therapy for dry eye.12 However, the efficacy of EGF eye drops on dry eye has not been adequately discussed so far. The aim of this study was to investigate the therapeutic effects of EGF on the mouse dry eye models induced by topical administration of benzalkonium chloride (BAC)13,14 and the mechanisms underlying these effects.” (Xiao et al, page 191., col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the temperature sensitive gel damage repair formulation of Kim et al., Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. to repair cornea damage as described by Xiao.
A person of ordinary skill in the art would be motivated to prevent the negative outcomes described by Xiao: “Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.” (Xiao, et al., page 191, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success based on how Kim and Xiao describe EFG being able to improve corneal repair and corneal health above.
Consequently, claim 13 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Xiao et al. and rejected.
Claims 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Kim, et al. International journal of pharmaceutics 233.1-2:159-167. (2002)) in view of Akkari et al. (Akkari, et al Materials Science and Engineering: C 68: 299-307 (2016)), Sleep (Sleep, Darrell. Expert opinion on drug delivery 12.5: 793-812 (2015)), Higuchi et al. (Higuchi, et al. Current eye research 32.2: 83-88 (2007)), Pavani et al. (Pavani, et al. Journal of Molecular Liquids 331: 115753 (2021)), Platts et al. (Platts, e al. International Journal of Pharmaceutics 486.1-2: 131-135 (2015)) and Rusciano et al. (Rusciano, et al. European journal of pharmacology 787: 9-19 (2016)) as applied to claim 1 above, and further in view of Pflugfelder et al. (Pflugfelder, et al. Experimental eye research 201: 108295 (2020)).
Regarding claim 11, claim 1 is obvious as describe above. Claim 11 further recites an application of the temperature sensitive gel damage repair formulation according to claim 1in preparing a drug for preventing, alleviating or treating keratoconjunctivitis sicca.
Pflugfelder discloses that inflammation and epithelial damage to the cornea leads to keratoconjunctivitis sicca:
“The lacrimal functional unit (LFU) regulates tear production, composition, distribution and clearance to maintain a stable protective tear layer that is essential for maintaining corneal epithelial health. Dysfunction of the LFU, commonly referred to as dry eye, leads to increased tear osmolarity and levels of inflammatory mediators in tears that cause ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS). Corneal changes in KCS include glycocalyx loss, barrier disruption, surface irregularity inflammatory cytokine/chemokine production, cornification and apoptosis.” (Pflugfelder, et al., page 108294, Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to use the formulation of Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. in preparing a drug to prevent, treat, or alleviate keratoconjunctivitis sicca as described by Pflugfelder et al. to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use the formulation in such a drug because the present specification shows that the formulation of claim 1 can repair corneal epithelial damage (Specification, para. [00105]). Cornea damage can lead to keratoconjunctivitis which in turn leads to stomal haze and pain: “While conjunctival disease decreases secretion of tear stabilizing mucins, corneal epithelial disease can impact visual quality, lead to stromal haze and cause pain(Khimani et al., 2020; Pflugfelder, 2011). Tear dysfunction is among the most common causes of corneal epithelial disease.” (Pflugfelder et al., page 108294, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success for similar reasons. Prevention or reversal of the corneal damage should prevent or alleviate keratoconjunctivitis sicca based on the causal relationship described by Pflugfelder above.
Consequently, claim 11 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Pflugfelder et al. and rejected.
Regarding claim 14, claim 1 is obvious as describe above. Claim 14 further recites an application of the temperature sensitive gel damage repair formulation according to claim 1 for or treating keratoconjunctivitis sicca and/or keratitis.
Pflugfelder discloses that inflammation and epithelial damage to the cornea leads to keratoconjunctivitis sicca:
“The lacrimal functional unit (LFU) regulates tear production, composition, distribution and clearance to maintain a stable protective tear layer that is essential for maintaining corneal epithelial health. Dysfunction of the LFU, commonly referred to as dry eye, leads to increased tear osmolarity and levels of inflammatory mediators in tears that cause ocular surface epithelial disease, termed keratoconjunctivitis sicca (KCS). Corneal changes in KCS include glycocalyx loss, barrier disruption, surface irregularity inflammatory cytokine/chemokine production, cornification and apoptosis.” (Pflugfelder, et al., page 108294, Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to use the formulation of Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. in preparing a drug to prevent, treat, or alleviate keratoconjunctivitis sicca as described by Pflugfelder et al. to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use the formulation in such a drug because the present specification shows that the formulation of claim 1 can repair corneal epithelial damage (Specification, para. [00105]). Cornea damage can lead to keratoconjunctivitis which in turn leads to stomal haze and pain: “While conjunctival disease decreases secretion of tear stabilizing mucins, corneal epithelial disease can impact visual quality, lead to stromal haze and cause pain(Khimani et al., 2020; Pflugfelder, 2011). Tear dysfunction is among the most common causes of corneal epithelial disease.” (Pflugfelder et al., page 108294, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success for similar reasons. Prevention or reversal of the corneal damage should prevent or alleviate keratoconjunctivitis sicca based on the causal relationship described by Pflugfelder above.
Consequently, claim 14 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Pflugfelder et al. and rejected.
Claims 12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Kim, et al. International journal of pharmaceutics 233.1-2:159-167. (2002)) in view of Akkari et al. (Akkari, et al Materials Science and Engineering: C 68: 299-307 (2016)), Sleep (Sleep, Darrell. Expert opinion on drug delivery 12.5: 793-812 (2015)), Higuchi et al. (Higuchi, et al. Current eye research 32.2: 83-88 (2007)), Pavani et al. (Pavani, et al. Journal of Molecular Liquids 331: 115753 (2021)), Platts et al. (Platts, e al. International Journal of Pharmaceutics 486.1-2: 131-135 (2015)) and Rusciano et al. (Rusciano, et al. European journal of pharmacology 787: 9-19 (2016)) as applied to claim 1 above, and further in view of Yang, Shaowei, et al. "Efficacy of topical recombinant human epidermal growth factor for treatment of diabetic foot ulcer: a systematic review and meta-analysis." The international journal of lower extremity wounds 15.2 (2016): 120-125.
Regarding claim 12, claim 1 is obvious as described above. Claim 12 recites an application of the temperature sensitive gel damage repair formulation according to claim 1 in preparing a drug for treating skin epidermal trauma, abrasions or ulcers.
Yang et al. discloses that human epidermal growth factor is known to be efficacious against skin ulcers: “In summary, our meta-analysis strengthens the finding that rhEGF is beneficial in treating diabetes wound ulcers by increasing the rate of wound healing. It also suggests rhEGF is beneficial, independent of the form in which the compound is applied to the wound. These findings support the use of rhEGF in treating these ulcers. Additional studies are needed to assess the effects of rhEGF alone or in combination with other growth factors or wound dressing agents.” (Yang et al., page 124, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to use the formulation of Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. in preparing a drug to treat skin ulcers as described by Yang et al. to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use the formulation in such a drug because Yang discloses that: “Among those with diabetes mellitus, about 20% of the patients will have diabetic foot ulceration during their lifetime, a common and serious complication of diabetes. Unfortunately, about 20% of patients with diabetes require amputation of some kind.” (Yang et al, page 120, col. 1 , para. 1). A person of ordinary skill in the art would seek to prevent such amputations.
A person of ordinary skill in the art would have a reasonable expectation of success because Yang discloses that EGF treatment can help heal skin ulcers as discussed above.
Consequently, claim 12 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Yang et al. and rejected.
Regarding claim 15, claim 1 is obvious as described above. Claim 12 recites an application of the temperature sensitive gel damage repair formulation according to claim 1 for treating skin epidermal trauma, abrasions or ulcers.
Yang et al. discloses that human epidermal growth factor is known to be efficacious against skin ulcers: “In summary, our meta-analysis strengthens the finding that rhEGF is beneficial in treating diabetes wound ulcers by increasing the rate of wound healing. It also suggests rhEGF is beneficial, independent of the form in which the compound is applied to the wound. These findings support the use of rhEGF in treating these ulcers. Additional studies are needed to assess the effects of rhEGF alone or in combination with other growth factors or wound dressing agents.” (Yang et al., page 124, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to use the formulation of Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. in preparing a drug to treat skin ulcers as described by Yang et al. to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use the formulation in such a drug because Yang discloses that: “Among those with diabetes mellitus, about 20% of the patients will have diabetic foot ulceration during their lifetime, a common and serious complication of diabetes. Unfortunately, about 20% of patients with diabetes require amputation of some kind.” (Yang et al, page 120, col. 1 , para. 1). A person of ordinary skill in the art would seek to prevent such amputations.
A person of ordinary skill in the art would have a reasonable expectation of success because Yang discloses that EGF treatment can help heal skin ulcers as discussed above.
Consequently, claim 15 is obvious over Kim et al. in view of Akkari et al., Sleep, Higuchi et al., Pavani et al., Platts et al. and Rusciano et al. as applied to claim 1 above, further in view of Yang et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-21 are rejected.
Claims 8 and 16-21 are objected to.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654