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 .
This Office Action is in reply to Applicants’ correspondence of 07/02/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 12/02/2025 Applicants elected, with traverse, the particular species that are (1) levels of peptides as a marker; and (2) the particular marker that is Ang(1-7).
The species election requirement applied among the different types of measurements modes (e.g.: levels of one or more peptides, gene expression levels of one or more genes) as recited in claims 1, 14 and 18 was WITHDRAWN as set forth on pages 2-3 of the Office Action of 03/06/2026.
The species election requirement directed to different particular biomarkers was deemed proper and made FINAL as set forth on page 2 of the Office Action of 03/06/2026.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
Any rejections of claims made under 35 USC 112b in the previous Office Action of 03/06/026 which are not reiterated below are withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 112 – Indefiniteness
Modified as Necessitated by Claim Amendments
Claims 1-9 and 22 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.
Claims 1-9 and 22 are unclear over recitation of the limitation “after the concentration of the one or more biomarkers returns to a predetermined threshold”, as recited in claim 1 from which claims 2-9 depend. The limitation is unclear because the claim sets forth measuring biomarker concentrations in a plurality of samples (i.e.: a first sample; one or more subsequent samples), so it is not clear which concentration is required to return to a threshold. The limitation is further unclear because there is no practical step of comparing any concentration to some standard, or requiring a determination that a concentration has changed from a threshold value, so it is unclear how the steps of the claimed methods are intended to require that some concentration has returned to a threshold (e.g.: there is no step of detecting an alteration of a biomarker level).
Response to Remarks
Applicants have traversed the rejections of claims under 35 USC 112(b) as unclear as maintained above. Applicants’ arguments (p.8-9 of the Remarks of 07/02/2026) have been fully and carefully considered but are not persuasive to withdraw the rejection.
With regard to the rejection of claims 1-9 and 22, Applicants have argued that the claims in light of the specification are clear to one of skill in the art where the specification teaches changes in biomarkers after photobiomodulation laser therapy of the retina. The argument is not persuasive. Initially it is noted that while the specification may inform the subject matter of the claims, it is improper to import into a claim limitations from the specification that are not part of the claim (see MPEP 2111.01(II)).
The Examiner maintains that the limitations of the claims are unclear. For example, where claim 1 recites “the concentration of the one or more biomarkers returns to a predetermined threshold”, such a limitation requires that a concentration is changed after treatment, and then that change is somehow diminished (i.e.: for something to “return” there is some requirement that it was initially changed). But where claim 1 encompasses the analysis of only a single sample after treatment (i.e.: “obtaining one or more subsequent samples” includes obtaining only a single sample), it is unclear how the conclusion that the level “returns” is intended to be made in the scope of the claims. The Examiner further maintains that this requirement is unclear where the claims do not set forth any requirements for any threshold (e.g.: only claim 2 defines any aspect of a threshold).
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claim 25 is 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.
Claim 25 is unclear over recitation of the limitation “determining that the eye is ready for a subsequent treatment based on the concentration of Ang(1-7) in the one or more subsequent samples returning toward the initial concentration”, as in light of the limitation “obtaining one or more subsequent samples from the biomatrix of the patient after the initial treatment”. The claim is unclear in so far as it specifically encompasses a single subsequent sample. The claim requires a determining that the concentration of Ang(1-7) is “returning towards the initial concentration”. But such a determination can not be made from a measurement of a single subsequent sample, as encompassed by the claims. The analysis of a single sample may show that the concentration is different than the initial sample, but is not indicative of the trajectory of any change in the concentration. Furthermore if the concentration in a singe subsequent sample is the same as the initial concentration there is no requirement that the concentration ever in fact changed after treatment, and as such it is unclear how such a concentration is “returning toward” a concentration from the initial sample.
Maintained Claim Rejection - Improper Markush Group
Modified as Necessitated by Claim Amendments
Claims 1-9, 15, 20, and 21 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117(II).
The Markush grouping of:
one or more peptides that include matrix metalloproteases (MMP), tissue inhibitors of metalloproteases (TIMPs), RAAS components including, but not limited to, Ang(1- 9), AngII, Ang(1-7), Ang(1-10), MasR, AT1R, AT2R, angiotensin converting enzyme-1 (ACE1), ACE2, neprilysin (NEP), aminopeptidase isoforms, or combinations thereof
As encompassed by claims 1 (from which claims 2-9 depend) and claims 15 and 20, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 2117(II)).
Herein, the recited alternative species do not share a single structural similarity, as each different biomarker (i.e.: the different recited proteins and peptide fragments) each have a different chemical structure in that each may consists of a different amino acid sequence. The only structural similarity present is that all of different elements comprise amino acids. The fact that the biomarkers comprise amino acids does not per se support a conclusion that they have a common single structural similarity because the structure of comprising amino acids is not essential to the asserted common activity of being correlated with retina damage resulting from laser eye treatment. Accordingly, while the different biomarkers are asserted to have the property of being correlated with retina damage resulting from laser eye treatment, they do not share a substantial structural similarity essential to this activity.
Further, there is no expectation from the knowledge in the prior art that proteins (generically), or the particular different elements of the Markush group, behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited biomarkers possess the common property of being correlated with retina damage resulting from laser eye treatment. For example, the specification teaches the analysis of biomarker expression in treated samples, and provides that “… R:GEN laser treatment had minimal effects on gene expression”; (para 0047); “.. no changes in MMP9 were detected” (para 0048). Furthermore, the different biological functionalities of the different markers (e.g.: Ang II is the primary effector of the “classical” RAS axis, promoting vasoconstriction and inflammation; whereas Ang-(1-7) acts as an antagonist to these effects, promoting vasodilation and anti-fibrotic actions) would provide the skilled artisan with knowledge from the art that members of Markush group may not behave in the same way in the context of the claimed invention and could not necessarily be substituted one for the other, with the expectation that the same intended result would be achieved (Alenina et al (2015)).
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to Remarks
Applicants have traversed the rejection of claims, which recite distinct biomarkers in the alternative, as directed to an improper Markush style grouping of alternative elements.
Initially it is noted that the rejection as maintained above is not applied to newly presented claims 21-14 which recite the angiotensin peptides Ang(1-9), AngII, Ang(1-7), and Ang(1-10).
Applicants’ arguments (p.9-10 of the Remarks of 07/02/2026) have been fully considered but are not persuasive to withdraw the rejection. Applicants have argued:
The matrix metalloproteases and tissue inhibitors of metalloproteases are art-recognized classes of the extracellular-matrix remodeling system, and the recited angiotensin peptides, receptors, and converting enzymes are members of the renin-angiotensin-aldosterone system. The recited members share a common use in the claimed methods as biomarkers of the retinal healing response following laser eye treatment.
This argument is not persuasive. Initially it is noted that the argument does not assert that the different elements that are “matrix metalloproteases and tissue inhibitors of metalloproteases”, and the different elements that are “angiotensin peptides, receptors, and converting enzymes” are part of the same recognized class. Furthermore, the argument does not fully address the issue of a “single structural similarity” as provided by the guidance of MPEP 2117(II)(A) (emphasis added):
… a Markush grouping is ordinarily proper if all the members of the group belong to a recognized class (whether physical, chemical, or art recognized) and are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed invention, and it is clear from their very nature or from the prior art that all members possess this property.
In the instant case the Examiner maintains that the group of alternative elements includes proteins that do not in fact contain a single structural similarity (e.g.: some share protein sequence or motif among matrix metalloproteases and angiotensin receptors); they are distinct proteins with distinct biological activities. And where Applications assert that the common use of the different elements is “as biomarkers of the retinal healing response following laser eye treatment”, the Examiner maintains that it is not clear from their very nature, or from the prior art, that all members (either of the asserted class, or of the elements of the Markush group) possess this property. The asserted association between biomarker concentration and retinal healing is established only by the experimentation of the instant application, not by the “very nature” of the different biomarker, and not established by the prior art.
The Examiner maintains that reference to the teachings of the specification (i.e.: paras 47-48) that some biological elements encompassed by the Markush group do not in fact display alteration in expression/concentration that is dependent upon retinal healing response following laser eye treatment is germane to the maintained rejection. The teachings of the specification provide evidence that the asserted common use of any elements as a biomarkers of the retinal healing response following laser eye treatment can only be established empirically, and is not tied to any structural similarity or categorization into a class. The Examiner is not persuaded by Applicants’ argument that “a measured absence of change is itself a quantitative biomarker result”. There are tens of thousands of genes and proteins in a biological organism, and most of them are not associated with the healing of the retina. To assert that a lack of any significant change in detected amount in response to treatment is evidence of some common useability of the different elements is contradictory to the assertion that the recited members share a common use in the claimed methods as biomarkers of the retinal healing response following laser eye treatment.
Withdrawn Claim Rejections - 35 USC § 101
The rejection of claims made under 35 U.S.C. 101 as set forth on pages 8-10 of the Office Action of 03/06/2026 is withdrawn in light of the amendments to the claims.
Maintained Claim Rejections - 35 USC § 112 – Scope of Enablement
Modified and Newly Applied as Necessitated by Claim Amendments
Claims 1-25 are 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:
Methods of guiding treatment of a patient’s eye comprising detecting a level of Ang(1-7) peptide (as consonant with the Election) in a plasma or serum sample from a subject before performance of a treatment on the eye of the subject, obtaining plasma or serum samples from the subject after performance of a treatment on the eye of the subject, detecting a level of Ang(1-7) peptide in the plasma or serum sample from a subject obtained after performance of a treatment on the eye of the subject that is not increased as compared to the level of Ang(1-7) peptide in the plasma or serum sample obtained from the subject before performance of a treatment on the eye of the subject, and performing a subsequent treatment of a patient’s eye
does not reasonably provide enablement for the methods as claimed which generically encompass any biomarker, and any measure of the biomarker (e.g.: activities, gene expression levels such as mRNA), any biomatirx sample, and any type of blood sample (e.g.: PBMCs, blood cellular components). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the invention and the breadth of the claims
The rejected claims are directed to methods of guiding eye treatment based on detecting a level of a biomarker in a sample after an initial treatment where the level of the biomarker returns to a threshold, or to a pretreatment level, as an indicator the patient is ready for a subsequent treatment. The claims encompass the detection of any biomarker (e.g.: claim 18 and 19 are generic with regard to the biomarker of the method), and detection of the biomarker using any measure (e.g.: peptide levels, activity levels, gene expression level such as mRNA). The claims further encompass the use of any biomatrix sample, or any portion of a blood sample. The claims thus encompass the detection of a wide variety of possible biomarker elements in providing guidance that a subject is suitable for a subsequent treatment.
Direction provided by the specification and working example
The instant application provides examples (p.15 of the specification) of the analysis of biomarkers in samples obtained from subject before and after Q-switched Nd:YLF laser treatment of the retina. Relevant to the breadth of the claims, the specification teaches (p.16, p.18) the analysis of biomarkers in retinal tissue using RT-PCR of the specification; and teaches (p.19) the analysis of circulating RAAS-related peptides in serum samples from subjects. Relevant to the Election, the specification teaches that Ang(1-7) is a marker for active healing response in treated subjects, and is circulating Ang(1-7) is detected increased levels in in samples of treated subject as compared to non-treated control levels.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to the detection and analysis of biomarker levels in any sample is high, the unpredictability in associating any particular level with suitability for subsequent treatment of a subject is higher.
Because the claims encompass the detection of Ang(1-7) in any biomatrix (e.g claim 1, as consonant with the election), or the detection of any biomarker in a blood sample (e.g.: claim 18) it is relevant to point out the unpredictability associated with the breadth of the claims.
Because the claims encompass the detection of Ang(1-7) in any biomatrix, while only teaching the detection of circulating Ang(1-7) levels as relevant to suitability for subsequent treatment, it is relevant to point out the unpredictability in extrapolating biomarker levels among different sample types. For example, Wilson et al (2023) teaches that protein levels in serum are not typically correlated with aqueous humor or vitreous humor levels, and even when considering aqueous humor protein levels to vitreous humor levels, there are many proteins that do not have correlated levels (Figs 1 and 2). Similar teachings of unpredictability are provided by Youngblood et al (2019). And where the claims encompass any portion of a blood samples, and particular include cellular components and PBMCs, while teaching only the analysis of circulating biomarkers it is relevant to point out that different portions of a blood sample (e.g.: serum versus blood cells) from the same subject may show different levels of biomarkers (Lepper (2017)).
The specification further shows the unpredictability in requiring an association between a marker and guidance that a subject is suitable for subsequent treatment, where the specification teaches failure to find an association between some expected marker levels and treatment (e.g.: “… R:GEN laser treatment had minimal effects on gene expression”; (para 0047); “.. no changes in MMP9 were detected” (para 0048)).
Additionally it is noted that while the specification teaches detection of gene expression levels (i.e.: mRNA detected via RT-PCR) of some markers, and peptide levels of other biomarkers, while the claims encompass any detection methods (e.g.: different biological molecules as analytes); Chen (2002) teaches that it is common for protein expression to be discordant with mRNA expression levels even in matched samples (e.g.: Figure 3). Thus, it is unpredictable as to how to extrapolate a detection exemplified by the teachings of the specification to detection of a different analyte. Similarly in this regard it is noted that different angiotensinogen peptides are created from the same precursor protein, and so measurement of an angiotensinogen mRNA may not be indicative of the level of the particular Ang(1-7) marker (consonant with the Election).
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Such experimentation would require case:control analysis of any analytes of any biomarkers from any biomatrix samples of interest to try to establish the broadly required associations of the claims where the level is increased after treatment and is suitable for guiding a subsequent treatment of the subject. Even if such experimentation were to be performed, given the unpredictability of the subject matter of the claims, there is no assurance that the required associations would beyond those specifically disclosed in the application would be detected.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention in the full scope as claimed.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112(a) as encompassing subject matter not enabled by the application as originally filed, as maintained above. Applicants’ arguments (p.11-12 of the Remarks of 07/02/2026) have been fully considered but are not persuasive to withdraw the rejection. The arguments assert that where the specification teaches RT-PCR for MMP2, MMP3, MMP9, and TIMP2 in retinal pigment epithelium; RT-PCR for ACEI, ACE2, AT1R, AT2R, and MasR in retinal-layer and RPE-layer tissue; and quantitative metabolomic LC-MS measurement of circulating Ang(1-9), AngIl, and Ang(1-7) peptides, the working examples of the specification cover multiple categories of biomarkers, measurement methods, and biomatrix types. In this regard it is first noted that Applicants’ species election is particular to the Ang(1-7) peptide.
Where The rejection points to the unpredictability in extrapolating expression levels among different sample types, the Applicants have argued that “the claims do not recite correlating biomarker levels across multiple sample types”. This argument is not persuasive because the claims generically encompass any biomatrix sample for the analysis of particular biomarkers. The Examiner maintains that in light of the evidence of Wilson et al and Youngblood et al, as cited in the rejection, it is unpredictable whether or not the particular exemplifications and results of the specification may be extrapolated among the different experimental methods. Thus while the specification teaches the analysis of MMP2 expression in retinal pigment epithelium using RT-PCR, and the specification teaches analysis of circulating Ang(1-7) peptides, such teachings would not lead the skilled artisan to conclude that analysis of Ang(1-7) in retinal pigment epithelium would have the same association with retinal healing, where such an association is encompassed by the claimed methods. Similar, there is simply no evidence that circulating MMP2 protein or MMP2 mRNA, as encaompssed by the claims, is reliably associated with retinal healing.
Similarly, the Examiner has cited Chen as evidence that extrapolating between mRNA expression levels and protein expression levels is unpredictable. Applicants have argued that the different measurement options of the claims are tied to a specific analyte type, and one of ordinary skill applies the recited method to a particular recited analyte category. But this argument fails to recognize the teachings of the cited art of Chen. While one may be able to detect Ang(1-7) (consonant with the election) peptide, and may also be able to detect some mRNA encoding an Ang(1-7) peptide, based on the teachings of Chen one would not expect that the association between the peptide levels and retinal healing (as taught by the specification) to necessarily be the same for an Ang(1-7) mRNA and retinal healing.
Applicants have next addressed the Examiner’s assertion that the teachings of the specification (i.e.: where no changes in MMP9 were detected in response to retinal damage or healing) establish the unpredictability in associating any biomarker (as encompassed by claims 10 and 18) with retinal healing indicative of readiness for a subsequent treatment. Applicants have argued that “the methodology is enabled to detect both changes and non-changes, which is the functional requirement of a quantitative biomarker assay”. But this argument is not persuasive. The claims require that, in response to an eye treatment, a biomarker level is altered, and that a decrease in this alteration (i.e.: the level returning to a pre-treatment level) indicates readiness for a subsequent eye treatment. A biomarker that does not change in response to treatment would not be suitable for the claimed methods, but where the claims generically encompass any biomarkers (e.g.: any biomarker as encompassed by claim 10), or broadly encompass any biomarker of a class (e.g.: any MMP, as recited in claim 1), it is entirely unpredictably which of the encompassed biomarkers will in fact be changed in response to treatment and are suitable for indicating readiness for a subsequent eye treatment.
The Examiner maintains that the breadth of the claims with regard to type of analyzed samples, different biomarkers, and different types of analyte detections, in light of the particular teachings of the specification, encompass subject matter which was not enabled by the related art or the teachings of the application as filed.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims under 35 U.S.C. 103 as set forth on pages 14-15 of the Office Action of 03/06/2026 is withdrawn in light of the amendments to the claims.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights