DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
2. Applicant’s amendments to the claims filed 07/13/2023 is acknowledged. Claims 1-17 are cancelled. Claims 18-34 are under review and pending.
Priority
3. The instant application was effectively filed on 07/13/2023, is a 371 of PCT/KR2021/000564 filed 01/14/2021.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 7/13/2023, 7/26/2023, 12/20/2024, 12/27/2024, and 01/21/2026 and the references cited therein have been considered, unless indicated otherwise.
Specification
5. Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length.
The Applicant’s abstract has surpassed the 150-word count limit. Appropriate correction is required.
Claim Objections
6. Claim 27 objected to under 37 CFR 1.75 as being a substantial duplicate of claim 26. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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.
7. The phrase “or more” in claims 19, 24, 25, 28, 29, and 30 is a relative phrase which renders the claim indefinite. The phrase “or more” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The phrase or more introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 18, 20, 21, 22, 31, 32, and 34 are rejected under 35 U.S.C 102(a)(1) as being anticipated over Harbour BioMed (Harbour BioMed Announces Completion of Phase 2 Study of HBM9036 in Patients with Moderate-to-Severe Dry Eye Disease in China. (https://www.harbourbiomed.com/news/29.html, available October 11, 2019)
The instant claims are drawn to a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye.
Harbour BioMed teach completion of Phase 2 study of HBM9036 (tanfanercept), a new investigational TNF receptor-1 fragment, in adult patients with moderate-to-severe Dry-Eye-Disease. Instant claim 18 teaches a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye. This recites the limitation of instant claim 18.
Harbour BioMed further teach 100 patients were randomized to receive 0.25% HBM9036 or vehicle control, administered as eye drops, to moderate-to-severe DED patients, twice a day for 8 weeks. Instant claims 31, 32 and 34 teach the ophthalmic composition is administered in the form of an eye drop once or more a day, twice a day, and comprises 0.01 to 1% of tanfanercept. This recites the limitations of instant claims 31, 32 and 34.
Harbour BioMed teach significant improvement of signs within 8 weeks were measured by Corneal Staining Score, a measure of corneal damage. Instant claims 20, 21, and 22 teach improvement of sign of the moderate-to-severe dry eye begins to appear within 8 weeks after administration of the ophthalmic composition and is determined on the basis of reduction in a total corneal staining score (TCSS) and a central corneal staining score (CCSS). Harbour Biomed teach total Corneal Staining Score which includes staining score and central corneal staining score. This teaches the limitations of instant claims 20, 21 and 22. Harbour BioMed anticipates the claimed invention.
9. Claims 18, 26-27 and 34 are rejected under 35 U.S.C 102(a)(1) as being anticipated over HanAll BioPharma Co., Ltd. (A Study to Assess Efficacy and Safety of HL036 in Subjects With Dry Eyes (VELOS-2). (https://clinicaltrials.gov/study/NCT03846453?term=NCT03846453&rank=1&tab=study&a=5#more-information, available March 11, 2019 and the information available at that date included study status, out measures and recruitment status)
The instant claims are drawn to a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept (0.01 to 1% (w/v)) as an active ingredient, to a patient with moderate-to-severe dry eye and patient are required to have Schirmer’s tear test score of 1 to 7 before administration.
HanAll BioPharma Co., Ltd. teach the safety and efficacy of 0.25% HL036 Ophthalmic Solutions (tanfanercept) to placebo for the treatment of the signs and symptoms of dry eye. Instant claim 18 and 34 recite teaches a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept (0.01 to 1%) as an active ingredient, to a patient with moderate-to-severe dry eye This teaches the limitations of instant claim 18 and 34.
HanAll BioPharma Co., Ltd. teach the primary outcome measures for the study are mean change from baseline to Visit 6 of Inferior Corneal and Conjunctival Staining Scale (ICSS) and mean change from baseline to Visit 6 of Ocular Discomfort Scale (ODS). HanAll BioPharma Co., Ltd. further teach the patient has a Schirmer's Test score of ≤ 10 mm and ≥ 1 mm at Visits 1 and 2. Instant claims 26-28 teach the patient has a Schirmer's tear test (STT) score of 1 to 7 before administration of the ophthalmic composition. HanAll BioPharma Co., Ltd. anticipates the claimed invention.
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.
10. Claims 18-23, 26-27, 31-32 and 34 are rejected under 35 U.S.C. 103 as being
unpatentable over Harbour BioMed (Harbour BioMed Announces Completion of Phase 2 Study of HBM9036 in Patients with Moderate-to-Severe Dry Eye Disease in China) in view of
Karakus, et al. (Sezen Karakus, Esen K. Akpek, Devika Agrawal, Robert W. Massof; Validation of an Objective Measure of Dry Eye Severity. Trans. Vis. Sci. Tech. 2018;7(5):26. https://doi.org/10.1167/tvst.7.5.26.).
The instant claims are drawn to a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye.
Harbour BioMed teach completion of Phase 2 study of HBM9036 (tanfanercept), a new investigational TNF receptor-1 fragment, in adult patients with moderate-to-severe Dry-Eye-Disease. Instant claim 18 teaches a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye. This recites the limitation of instant claim 18. Harbour BioMed further teach 100 patients were randomized to receive 0.25% HBM9036 or vehicle control, administered as eye drops, to moderate-to-severe DED patients, twice a day for 8 weeks. Instant claims 31, 32 and 34 teach the ophthalmic composition is administered in the form of an eye drop once or more a day, twice a day, and comprises 0.01 to 1% of tanfanercept. This recites the limitations of instant claims 31, 32 and 34. Harbour BioMed teach significant improvement of signs within 8 weeks were measured by Corneal Staining Score, a measure of corneal damage. Instant claims 20, 21 and 22 teach improvement of sign of the moderate-to-severe dry eye begins to appear within 8 weeks after administration of the ophthalmic composition and is determined on the basis of reduction in a total corneal staining score (TCSS) and a central corneal staining score (CCSS). Harbour Biomed teach total Corneal Staining Score which includes staining score and central corneal staining score. This teaches the limitations of instant claims 20, 21 and 22.
Harbour Biomed do not teach baseline Schirmer’s tear test of 1 to 7 before administration, baseline total corneal staining score of 5 more before administration, baseline central corneal staining score of 2 or more, baseline eye dryness score of 40 or more before administration, baseline ocular discomfort score of 5 or more before administration (ODS).
However, Karakus, et al. teach a single dry eye severity measure was estimated using six clinical tests including 1-minute Schirmer’s test, 5 minute Schirmer’s test, corneal staining, conjunctival staining and each of the 12 OSDI questions were defined to be a separate indicator variable. Karakus, et al. further teach that standard dry eye clinical signs and symptoms can work together to define and measure a dry eye disease severity variable. Karakus, et al. also teach there is no single best dry eye severity measure.
Both Harbour Biomed and Karakus et al teach ocular assessments. Harbour Biomed teach the conventional eye drop assessment measured by Corneal Staining Score. One of ordinary skill in the art would reasonably include the conventional dry eye severity assessments taught by Karakus, et al. One of ordinary skill in the art, seeking to implement or optimize the method of treatment taught by Harbour BioMed would have been motivated to apply the conventional dry eye severity assessment framework taught by Karakus, et al. in order to objectively identify patients having moderate to severe dry eye disease and to ensure consistent baseline characterization of patient prior to treatment. Incorporating baseline thresholds for commonly used dry eye diagnostic parameters, such as Schirmer’s tear test values, corneal staining scores, and symptom-based dryness or discomfort scores, would have been predictable and routine modifications reflecting standard clinical practice. The combination of Harbour BioMed and Karakus, et al. applied known and conventional severity assessment techniques to a known method of treating dry eye disease with tanfanercept and does not require undue experimenting or produce an unexpected technical effect. Accordingly, it would have been obvious to one of ordinary skill in the art to arrive at the claimed method by combining the teachings of Harbour BioMed with the standard dry eye severity assessment methodologies described by Karakus, et al.
It would have been prima facie obvious at the time of the invention to combine the therapeutic use of tanfanercept for dry eye disease by Harbour BioMed with the composite dry eye severity framework disclosed in Karakus, et al., which teach that dry eye severity is a latent variable best estimated using multiple clinical signs and patient-reported symptoms rather than any single endpoint because Karakus, et al. teach that standard dry eye clinical signs and symptoms can work together to define and measure a dry eye disease severity variable. One of ordinary skill in the art could reasonably understand that a Schirmer’s tear of 1 to 7, TCSS of 5 or more, CCSS of 2 more, EDS score of 40 or more and ODS of 5 moreKSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
11. Claim(s) 24 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harbour BioMed in view of Karakus, et al as applied to claims 18-23, 26-27, 31-32 and 34 above, and further in view of EntoKey (“Reliability of 4 Clinical Grading Systems for Corneal Staining.” EntoKey, 8 Jan. 2017, entokey.com/reliability-of-4-clinical-grading-systems-for-corneal staining/#:~:text=The%20Oxford%20grading%20scale%20divides,multiplied%20by%20the%20density%20grade., available January 8, 2017)
Claim 24 is drawn to the method according to claim 18, wherein the patient has CCSS of 2 or more before administration of the ophthalmic composition.
Claim 25 is drawn to the method according to claim 18, wherein the patient has TCSS of 5 or more before administration of the ophthalmic composition.
The teachings of Harbour BioMed and Karakus, et al. are described above.
Although Harbour BioMed teaches moderate-to-severe dry eye disease, both Harbour Biomed and Karakus, et al. do not teach Central corneal staining score of 2 or more and total corneal staining score of 5 more.
However, EntoKey teaches that corneal staining grading system divides the cornea into 5 zones; central, superior, temporal, nasal, and inferior. Each zone is graded on a scale of 0 to 3, with 2 being graded as moderate (Four grading scales for corneal staining section). EntoKey teaches that the total TCSS is the total of all 5 corneal staining scores, which the maximum for severe is a total of 15 (Four grading scales for corneal staining section).
It would have been prima facie obvious at the time of the invention by one of ordinary skill in the art to reasonably conclude that the patients taught by the combination of Harbour BioMed and Karakus, et al would have a CCSS of 2 or more (claim 24) since Harbour BioMed discloses that the adult patients of their study have moderate-to-severe Dry-Eye-Disease and EntoKey teaches that moderate patients are given a score of 2 and severe patients are accessed a score of 3 on the corneal staining grading system. The TCSS for all 5 zones for moderate to severe patients would be a score of between 10 to 15. Therefore, the combination of references teach the claim limitation “wherein the patient has TCSS of 5 or more before administration of the ophthalmic composition” (claim 25). Harbour BioMed, Karakus, et al and EntoKey all teach dry eye disease diagnostics tests and tools to determine severity. EntoKey specifically teach that a score of 2 on the corneal staining grading system is classified as moderate. Therefore, one of ordinary skill in the art would understand that baseline scores of moderate-to-severe represent a known and accepted baseline in the art, from which experiment measurements and comparative analysis are made of. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
12. Claim(s) 28, 29, and 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harbour BioMed, Karakus, et al and Entokey as applied to claims 18-27, 31-32 and 34 above, and further in view of Holland, et al. (Holland EJ, Luchs J, Karpecki PM, Nichols KK, Jackson MA, Sall K, Tauber J, Roy M, Raychaudhuri A, Shojaei A. Lifitegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology. 2017 Jan;124(1):53-60. doi: 10.1016/j.ophtha.2016.09.025. Epub 2016 Oct 27. PMID: 28079022., available 10/27/2016).
Claim 28 is drawn to the method according to claim 18, wherein the patient has an ocular discomfort score (ODS) of 3 or more before administration of the ophthalmic composition.
Claim 29 is drawn to the method according to claim 18, wherein the patient has TCSS of 5 or more and ODS of 3 or more before administration of the ophthalmic composition.
Claim 30 is drawn to the method according to claim 18, wherein the patient has TCSS of 4 or more and EDS of 40 or more before administration of the ophthalmic composition.
The teachings of Harbour BioMed, Karakus, et al. and Entokey are described above.
Although Entokey et al discusses patients with a TCSS score of 5 or more, Harbour Biomed and Karakus, et al. and Entokey do not specifically teach the combined claimed limitations of ocular discomfort score (ODS) of 3 or more before administration of the ophthalmic composition, wherein the patient has TCSS of 5 or more and ODS of 3 or more before administration of the ophthalmic composition or wherein the patient has TCSS of 4 or more and EDS of 40 or more before administration of the ophthalmic composition.
However, Holland, et al. teach moderate to severe eye dryness score is a EDS of 40 or more (3rd paragraph). Holland, et al. further teach the ocular discomfort score (ODS) is graded on a 5- point integer scale from 0 being no discomfort to 4 being severe discomfort (outcome measures section). One of ordinary skill in the art would be able to reasonably conclude that an ODS score of 3 out of 4 would fall under moderate-to-severe.
It would have been prima facie obvious at the time of the invention by one of ordinary skill in the art to reasonably conclude that the patients taught by the combination of Harbour BioMed, Karakus, et al, Entokey and Holland et al would have a ODS of 3 or more (claim 28), a TCSS of 5 or more and ODS of 3 or (claim 29) and a TCSS of 4 or more and EDS of 40 or more and all scores are before administration of the ophthalmic composition because Harbour BioMed discloses that the adult patients of their study have moderate-to-severe Dry-Eye-Disease, Holland et al teach moderate to severe eye dryness score is a EDS of 40 or more and an ODS of 4 is severe discomfort and Entokey teaches TCSS scores over 4. Therefore, one of ordinary skill would reasonably conclude that the combination of references teach dry eye disease diagnostics tests and tools to determine severity of disease.
13. Claims 18, 20, 21, 22 31, 32, 33 and 34 are rejected under 35 U.S.C. 103 as being
unpatentable over Harbour BioMed (Harbour BioMed Announces Completion of Phase 2 Study of HBM9036 in Patients with Moderate-to-Severe Dry Eye Disease in China) in view of PowerPak, et al. (Compounding Preparations for Ophthalmic Use in Humans. PowerPak. (2018, April 21). https://www.powerpak.com/course/content/113227)
The instant claims are drawn to a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye.
Claim 33 is drawn to a method according to claim 18, wherein the ophthalmic composition comprises tanfanercept and a buffer system at pH 5.0 to pH 6.5, and the ophthalmic composition is substantially free of a stabilizer.
Harbour BioMed teach completion of Phase 2 study of HBM9036 (tanfanercept), a new investigational TNF receptor-1 fragment, in adult patients with moderate-to-severe Dry-Eye-Disease. Instant claim 18 teaches a method for treatment of dry eye syndrome, comprising administering an ophthalmic composition, which comprises tanfanercept as an active ingredient, to a patient with moderate-to-severe dry eye. This recites the limitation of instant claim 18. Harbour BioMed further teach 100 patients were randomized to receive 0.25% HBM9036 or vehicle control, administered as eye drops, to moderate-to-severe DED patients, twice a day for 8 weeks. Instant claims 31, 32 and 34 teach the ophthalmic composition is administered in the form of an eye drop once or more a day, twice a day, and comprises 0.01 to 1% of tanfanercept. This recites the limitations of instant claims 31, 32 and 34. Harbour BioMed teach significant improvement of signs within 8 weeks were measured by Corneal Staining Score, a measure of corneal damage. Instant claims 20, 21, and 22 teach improvement of sign of the moderate-to-severe dry eye begins to appear within 8 weeks after administration of the ophthalmic composition and is determined on the basis of reduction in a total corneal staining score (TCSS) and a central corneal staining score (CCSS). Harbour Biomed teach total Corneal Staining Score which includes staining score and central corneal staining score. This teaches the limitations of instant claims 20, 21 and 22.
Harbour Biomed does not teach a buffer system at pH 5.0 to pH 6.5, and the ophthalmic composition is substantially free of a stabilizer.
However, PowerPak, et al. teaches several factors must be considered when compounding ophthalmic preparations: chemical stability of the active drug(s), possible microbial contamination, incompatibilities, viscosity, pH and buffering, tonicity, particle size (if a suspension), final container (such as dropper bottle or syringe), compatibility with the eyes, appropriateness of the vehicle, and patient comfort and tolerability. PowerPak, et al. further teaches the buffer capacity should be less than 0.05 and maintain a pH range of 4 to 8 which includes the pH range taught by Harbour BioMed, et al. PowerPak, et al. also teaches Phenylmercuric nitrate which is used both as a preservation and stabilizer in ophthalmic solutions with a concentration of 0.004% (w/v). The Applicant defined “substantially free of a stabilizer” in the specification as 0.1% (w/v) or less (paragraph 51). PowerPak, et al. teach that these formulations, in order to be chemically stable, comfortable for the patient and tolerable, would be buffered within a pH range of about 4 to 8 and PowerPak, et al. further teach that formulations do not have to include stabilizers. PowerPak, et al. teach buffers are used in ophthalmics when the pH is critical and must be within a certain range and an optimum pH avoids adverse effects, ensures that drugs will produce an optimum therapeutic effect, and ensures all components' roles are optimized (pH and buffering agents section).
Based on the teachings of PowerPak, et al., one would reasonably conclude that optimization of buffers is possible depending on the patient population being treated. The time of dosage and measuring clinical endpoints can clearly be a result effective parameter that a person having ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the dosage and dosing regimen, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). 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,"(See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
It would have been prima facie obvious at the time of the invention by one of ordinary skill in the art to adjust the pH of the buffer as taught by PowerPak in the ophthalmic composition in the teaching of Harbour Biomed because PowerPak teaches teach buffers are used in ophthalmics when the pH is critical and must be within a certain range and an optimum pH avoids adverse effects, ensures that drugs will produce an optimum therapeutic effect, and ensures all components' roles are optimized (pH and buffering agents section). Because this known acceptable pH range fully encompasses the claimed pH range of 5.0 to 6.5, one of ordinary skill in the art would have been motivated to select an appropriate buffer system within this range as a matter of routine optimization with a reasonable expectation of success.
Accordingly, one of ordinary skill in the art would have been motivated to employ low or minimal amounts of stabilizer, including concentrations at or below 0.1% (w/v), as claimed, based on routine formulation choice. The combination of Harbour BioMed and PowerPak therefore represents the predictable use of prior elements according to their established functions and does not require undue experimentation. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Conclusion
14. No claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674