Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-2, 4-6, 11 and 13-15 are pending.
Claims 3, 7-10, 12 are cancelled.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/13/2026 has been entered.
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 1-2 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over BEUERMAN (US 8080428B2) in view of BAUDOUIN (Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting. Clinical Science. 2013.) and evidenced by RANCHO (Understanding Dry Eye Syndrome. 2019.).
Regarding claim 1, BEUERMAN teaches a method of diagnosing and treating dry mucosa, also called dry eye, in a subject (abstract). The method comprises providing a sample from a subject (claim 1), that has dry eye syndrome (column 9 paragraph 4). The expression of S100 A9 was measured (Claim 2), which reads on measuring an amount of a marker for a nerve abnormality in an eye present in the sample, wherein expression of the marker is correlated with at least one parameter selected from the group consisting of corneal nerve branch density (CNBD), corneal nerve fiber total branch density (CTBD), corneal nerve fiber length (CNFL). The expression levels were compared to reference values from control subjects that are not experiencing dry eye (Claim 1), which reads on comparing the measured amount of the marker with an amount of the marker in a sample obtained from a healthy individual to determine whether the subject has a nerve abnormality in the eye. Prolactin and/or androgen are administered to the subject to alleviate the symptoms of dry eye (Example 12), which reads on administering an effective amount of a drug.
BEUERMAN does not explicitly teach treating an eye nerve abnormality.
BAUDOUIN teaches a method of investigating dry eye disease in subjects with dry eye disease (page 251, paragraph 8). The tear film, lacrimal glands (main and accessory lacrimal glands, meibomian glands, goblet cells, and all ocular surface secretory cells), lacrimal outflow pathways, and corneal and conjunctival epithelia work together as a lacrimal functional unit (LFU) to maintain the tear film and protect the transparency of the cornea and the integrity of the ocular surface (page 247, paragraph 2). Disease or damage to any component of the LFU, such as the afferent sensory nerves, the efferent autonomic and motor nerves, and the tear-secreting glands, can destabilize the tear film and lead to ocular surface disease that expresses itself as dry eye disease (DED) (page 247, paragraph 2). This reads on an eye nerve abnormality.
Note dry eye disease is another name for dry eye syndrome as evidenced by RANCHO (page 1, paragraph 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate treating a nerve abnormality. The person of ordinary skill in the art would have been motivated to make those modifications, because as discussed above disease or damage to the nerves can destabilize the tear film and lead to ocular surface disease that expresses itself as DED, and reasonably would have expected success because the references are in the same field of endeavor, such as patients with dry eye syndrome.
Regarding claims 2, 4 and 5, BEAUERMAN measures S100 A9 (Claim 2). Applicant’s specification discloses protein S100-A9 has a correlation with the corneal nerve branch density, (CNBD and CTBD) and corneal nerve fiber length (CNFL) so that they are considered as markers which reflect the condition of nerve abnormality in the eye (Page 50, paragraph 2).
Regarding claim 6, BEUERMAN teaches a step of detecting the marker by reacting the marker with a chemical, such as an antibody (Column 3, paragraph 4).
BEUERMAN teaches that the method used for the detection, identification, and/or quantification at least one biomarker or a group of biomarkers in tear fluid of a subject provides the basis for diagnosing the condition of dry eyes due to any cause (Column 7).
Claim 11, 13 and 15 is rejected under 35 U.S.C. 103 as being unpatentable over BEUERMAN (US 8080428B2) in view of BAUDOUIN (Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting. Clinical Science. 2013.) and evidenced by RANCHO (Understanding Dry Eye Syndrome. 2019.) as applied to claims 1-2 and 4-6 above, and further in view of SORIA (Tear proteome analysis in ocular surface diseases using label-free LC-MS/MS and multiplexed-microarray biomarker validation. Scientific Reports. 2017.).
BEUERMAN, BAUDOUIN, and RANCHO teach Applicant’s invention as discussed above.
Regarding claim 11-in-part, BEUERMAN teaches a method of diagnosing and treating dry mucosa, also called dry eye, in a subject (abstract). The method comprises providing a sample from a subject (claim 1), which reads on obtaining a sample from the subject. The expression of multiple biomarkers were measured in the method including S100 A8 (Example 13), which reads on measuring an amount of a marker for dry eye present in the sample, wherein expression of the marker is correlated with at least one parameter selected from the group consisting of tear film break-up time (BUT), Ocular Surface Disease Index (OSDI), and Dry Eye Questionnaire 5 (DEQ5). The expression levels were compared to reference values from control subjects that are not experiencing dry eye (Claim 1), which reads on comparing the measured amount of the marker with an amount of the marker in a sample obtained from a healthy individual to determine that the subject has dry eye based on the amount of the marker. Prolactin and/or androgen are administered to the subject to alleviate the symptoms of dry eye (Example 12), which reads on administering an effective amount of a drug for treating or reducing a risk of dry eye to a subject determined to have dry eye.
Regarding claim 14, BEUERMAN teaches a step of detecting the marker by reacting the marker with a chemical, such as an antibody (Column 3, paragraph 4).
Regarding claim 15-in-part, BEUERMAN teaches a method of diagnosing and treating dry mucosa, also called dry eye, in a subject (abstract). The method comprises providing a sample from a subject (claim 1), which reads on obtaining a sample from the subject. The expression of multiple biomarkers were measured in the method including S100 A9 (Claim 2) and S100 A8 (Example 13), which reads on measuring an amount of a first marker in the sample that changes expression in correlation with at least one parameter selected from the group consisting of CNBD, CTBD, CNFD, CNFL, and corneal nerve tortuosity and an amount of a second marker in the sample that changes expression in correlation with at least one parameter selected from the group consisting of tear film break-up time (BUT, Ocular Surface Disease Index (OSDIJ, and Dry Eye Questionnaire 5 (DEQ5). The expression levels were compared to reference values from control subjects that are not experiencing dry eye (Claim 1), which reads on comparing the measured amounts of each of the first and second markers with respective amounts of the first and second markers in a sample obtained from a healthy individual to determine that the subject has dry eye based on the amounts of each of the first and second markers. Prolactin and/or androgen are administered to the subject to alleviate the symptoms of dry eye (Example 12), which reads on administering an effective amount of a drug for treating or reducing a risk of dry eye to a subject determined to have dry eye associated with a nerve abnormality.
Regarding claim 15-in-part, BAUDOUIN teaches a method of investigating dry eye disease in subjects with dry eye disease (page 251, paragraph 8). The tear film, lacrimal glands (main and accessory lacrimal glands, meibomian glands, goblet cells, and all ocular surface secretory cells), lacrimal outflow pathways, and corneal and conjunctival epithelia work together as a lacrimal functional unit (LFU) to maintain the tear film and protect the transparency of the cornea and the integrity of the ocular surface (page 247, paragraph 2). Disease or damage to any component of the LFU, such as the afferent sensory nerves, the efferent autonomic and motor nerves, and the tear-secreting glands, can destabilize the tear film and lead to ocular surface disease that expresses itself as dry eye disease (DED) (page 247, paragraph 2). This reads on an eye nerve abnormality.
Note dry eye disease is another name for dry eye syndrome as evidenced by RANCHO (page 1, paragraph 2).
Note, Applicant’s claim defines protein S100-A8 as having a correlation with at least one of the parameters listed in claims 11 and 15.
BEUERMAN, BAUDOUIN, and RANCHO do not teach measuring the expression of antileukoproteinase.
Regarding claim 11, 13, and 15, SORIA teaches that the expression of antileukoproteinase (SLPI) is used to analyze dry eye disease in subjects (abstract). The expression of S100-A8 is also used to analyze subjects for dry eye (Page 5, paragraph 7). The dry eye was determined using tear breakup time (page 3, paragraph 2).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate measuring the expression of antileukoproteinase. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because S100-A8 and antileukoproteinase are functional equivalents of biomarkers commonly measured for dry eye.
Response to Arguments
With regard to claim 1, nothing in the cited combination of references teaches or suggests comparing the measured amount of a marker selected from the list recited in claim 1 with an amount of the marker in a sample obtained from a healthy individual to determine whether the subject has a nerve abnormality in the eye, as recited in claim 1. With regard to claim 15, nothing in the cited combination of references teaches or suggests comparing the measured amounts of a first marker selected from the list recited in claim 15 and second marker selected from the list recited in claim 15 with respective amounts of the markers in a sample obtained from a healthy individual to determine that the subject has dry eye associated with a nerve abnormality based on the amounts of each of the first and second markers as recited in claim 15. The Examiner improperly relies on hindsight and teachings of the present application to correlate markers disclosed in Beuerman with an eye nerve abnormality, but a person of ordinary skill would not have understood from Beuerman or from the combination of Beuerman and Tepelus that the markers recited in claims 1 and 15 are useful for identifying an eye nerve abnormality. Nowhere does Beuerman teach or suggest that any of these markers are associated with eye nerve abnormality let alone that S100-A9, S100-A8 could be used in a method as claimed. In fact, Beuerman does not mention nerve function at all. Thus, contrary to the premise of the rejection, Beuerman does not teach or suggest comparing the measured amount of S100-A9 or S100-A8 to determine whether the subject has a nerve abnormality in the eye.
The Examiner does not find the argument persuasive because as discussed above, BEUERMAN teaches the method claimed by Applicant for dry eye syndrome. BAUDOUIN teaches that dry eye disease, also known as dry eye syndrome, is correlated to nerve disease or damage, which reads on eye nerve abnormality.
Furthermore, Applicant’s claim define the biomarkers listed, such as S100-A9 as a biomarker for eye nerve abnormality and BEUERMAN teaches analyzing S100-A9 in correlation with dry eye syndrome and BEUERMAN teaches that the method used for the detection, identification, and/or quantification at least one biomarker or a group of biomarkers in tear fluid of a subject provides the basis for diagnosing the condition of dry eyes due to any cause (Column 7).
The rationale underlying the rejection appears to be that because Beuerman reports that certain markers are associated with dry eye, and Tepelus reports that certain dry eye conditions can be associated with eye nerve abnormalities, there would be a reasonable expectation that markers useful for detecting dry eye would be useful for detecting eye nerve abnormality, but the cited references do not support such an extrapolation of Beuerman. Simply because A is correlated with B and certain subsets of B are correlated with C does not mean that A is correlated is C. As explained above, nothing in the cited references suggests that the specific markers identified in Beuerman as being associated with dry eye would be diagnostic of eye nerve abnormality. The rejection overlooks the fact that any of Beureman's markers that are elevated in subjects who have dry eye without eye nerve abnormality would not be useful in a method as claimed. In this regard, Applicant emphasizes that without the disclosure of the present application, a person of ordinary skill would not have had any reason to expect that any markers identified by Beuerman could be used to diagnose eye nerve abnormality, and certainly would not have been able to identify which of Beurman's markers also are associated with eye nerve abnormality. Without the teachings of the present application, it could be just as likely that Beureman's markers are elevated in subjects who have dry eye without eye nerve abnormality, in which case they would not be useful in a method as claimed.
The Examiner does not find the argument persuasive because In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In the instant case, as discussed above, BEUERMAN teaches the method claimed by Applicant for dry eye syndrome. BAUDOUIN teaches that dry eye disease, also known as dry eye syndrome, is correlated to nerve disease or damage, which reads on eye nerve abnormality.
Furthermore, Applicant’s claim define the biomarkers listed, such as S100-A9 as a biomarker for eye nerve abnormality and BEUERMAN teaches analyzing S100-A9 in correlation with dry eye syndrome and BEUERMAN teaches that the method used for the detection, identification, and/or quantification at least one biomarker or a group of biomarkers in tear fluid of a subject provides the basis for diagnosing the condition of dry eyes due to any cause (Column 7).
To the extent the rejection relies on the assertions at page 7 of the Office Action that "S100-A8 and antileukoproteinase are functional equivalents of biomarkers commonly measured for dry eye," Applicant notes that the cited references do not support that premise and no other supporting evidence was provided. To the extent this assertion stems from Soria, Applicant disagrees that Soria supports that premise. Just because Soria studied both markers in the context of MGD and DE does not mean Soria determined them to be "functional equivalents." Moreover, Soria does not teach or suggest that expression of S100-A8 is correlated with at least one parameter selected from the group consisting of tear film break-up time (BUT), Ocular Surface Disease Index (OSDI), and Dry Eye Questionnaire 5 (DEQ5). Thus, even if this rationale were substantiated it would not support rejection of claim 13.
The Examiner does not find the argument persuasive because SORIA teaches that the expression of antileukoproteinase (SLPI) is used to analyze dry eye disease in subjects (abstract). The expression of S100-A8 is also used to analyze subjects for dry eye (Page 5, paragraph 7). The dry eye was determined using tear breakup time (page 3, paragraph 2).
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. MEJIAS whose telephone number is (703)756-5666. The examiner can normally be reached M-F.
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/S.L.M./ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618
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