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 .
Election/Restrictions
Applicant's election with traverse of the particular species that are (1) levels of peptides as a marker; and (2) the particular marker that is Ang(1-7) in the reply filed on 12/02/2025 is acknowledged. The traversal (as set forth in the replies of 07/30/2025 and 12/02/2025) is on the ground(s) that the different recited markers are not patentably distinct because they are components of interconnected biological pathways, and collectively indicate the same physiological state of readiness for retreatment following laser therapy. This is not found persuasive because there is no requirement for the “collective” analysis of the different markers, where the claims are directed to subcombinations of the markers with recitation of the limitation “one or more biomarkers”. Additionally, while the different recited biomarkers may be broadly encompassed by similar pathways (e.g.: the Renin-Angiotensin-Aldosterone System (RAAS)), the different biomarkers may in fact have different biological functions (e.g.: causing opposing results of vasoconstriction or vasodilation). The Examiner maintain that the different biomarkers, and combinations and subcombinations thereof, are properly separated in the species election requirement.
The requirement is still deemed proper and is therefore made FINAL.
In light of the Examiner search and consideration of the elected species that is “levels of peptides” as a biomarker measurement (e.g.: relevant to Election I in the Requirement of 06/03/2025), the species election requirement applied among the different measurements as recited in claims 1, 14 and 18 is WITHDRAWN.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1-20 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 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).
Claims 10-17 are unclear over recitation of the limitation “identifying when the concentration of the one or more biomarkers in the second subsequent sample returns to a predetermined threshold nearer the initial concentration”, as recited in claim 10, from which claims 11-17 depend. The claim recites a relative limitation where the concentration in “the second subsequent” is “nearer the initial concentration”, but the claim does not set forth what the standard for “nearer” is. The claims may be made more clear in this regard if amended to set forth a step of identifying that the concentration in the second subsequent sample is nearer to the initial concentration than the concentration in the first subsequent sample is.
Claims 18-20 are unclear over recitation of the “identifying when the concentration of the one or more biomarkers in the subsequent biomarker samples return to the initial concentration” as recited in claim 18, from which claims 19 and 20 depend. The limitation is unclear because there is no practical step of comparing any concentrations (e.g.: between the first biomarker sample and the subsequent biomarker samples), or requiring a determination that a concentration has changed from a first sample concentration to any subsequent sample concentration, so it is unclear how the steps of the claimed methods are intended to require that some concentration has returned to an initial concentration (e.g.: there is no step of detecting an alteration of a biomarker concentration).
Claim Rejection - Improper Markush Group
Claims 1-10, 15 and 20 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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 10-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions including abstract ideas and natural phenomena without significantly more.
The claim(s) recite(s) methods of identifying and quantifying one or more biomarkers to guide treatment of a patient’s eye, and include a step of “identifying when the concentration of the one or more biomarkers in the second subsequent sample returns to a predetermined threshold nearer the initial concentration”. The claims are directed to an evaluation of data or information to reach a conclusion or make a judgment, which is a mental process that is an abstract idea (see MPEP 2106.04(a) III). Additionally, where indicate the relationship between marker concentration and suitability for treatment of a subject, the claims are directed to the natural association between biomarker content and phenotype (e.g.: relative peptide concertation and healed damage to a tissue), and thus are directed to a natural phenomenon (see MPEP 2106.04(b) I).
This judicial exception is not integrated into a practical application because the claims do not practically apply the judicial exception(s) noted above, by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 10 is directed to “identifying” a biomarker, is only an abstract idea of recognizing a quality or potential use of the measured concentrations.
Here it is noted that while some of the claims broadly recite steps of detecting a biomarker in samples, these steps are not considered to integrate the judicial exception(s) into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception (see MPEP 2106.05(g)).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s) because a step of detecting expression of a biomarker in in a sample is well understood, routine and conventional activity in the related prior art as demonstrated by the related prior art. Steps related to the analysis of biomarkers in samples taken before and after performance of a treatment were known in the art, as taught by Dunmire et al (2011). It is noted that the claims include the mixing of samples in compositions with protease inhibitors, which was well understood, routine and conventional in the art related to analysis of proteins in samples (e.g.: Yi et al (2011).
Claim Rejections - 35 USC § 112 – Scope of Enablement
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.
Claims 1-9 and 18-20 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 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.
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.
Claim(s) 10-14, 16 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dunmire et al (2011) in view of Yi et al (2011).
Relevant to the methods of the rejected claims, Dunmire et al teaches obtaining serum samples (p.780 – Sample collection) (relevant to claims 12 and 13) from subjects prior to an initial eye treatment, and multiple samples taken at different times after an initial eye treatment at 4 h, 1 day, and 3 days following a laser treatment (relevant to (p.780 – Laser treatment; Sample collection) (relevant to claim 16). The reference teaches measuring the concentration of biomarkers as levels of peptides in the samples (p.780- Sample preparation and mass spectrometry) (relevant to claim 14), and identifying in samples when the level of the biomarker has returned to the pre-treatment control level (e.g.: Figure 2) (relevant to claim 11).
Dunmire et al does not exemplify the mixing of each sample with a protease inhibitor, but such methods in the analysis of protein analytes in blood samples were known in the prior art and art taught by Li et al.
Li et al teaches that sample proteolysis causes ex vivo damage of sample proteins and peptides, and that adding samples to EDTA, as well as a cocktail of protease inhibitors (relevant to the limitations of claim 1 and 17) in a BD P100* blood collection tube enhances stability of proteins and peptides (e.g.: p.146).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have mixed the samples of Dunmire et al with EDTA and protease inhibitors as taught by Li et al. The skilled artisan would have been motivated to use, and would have had a reasonable expectation of success in using, EDTA and protease inhibitors based on the expressed teachings of Li et al that blood samples collected with EDTA and protease inhibitors have less degradation (Fig. 1; Fig. 2).
Conclusion
No claim is allowed.
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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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683