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 .
Status of the Claims
Claims 1-13 are pending in the application and are the subject of this office action.
Priority
The instant application is a 371 National Stage of PCT/EP2021/077267, filed 4 October 2021.
The instant application claims benefit of foreign application EP20306156.9, filed 5 October 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5 April 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Embedded hyperlink and/or other forms of browser executable code is found at at least:
Specification Pg. 26, Ln. 8
Claim Objections
The use of the phrasing “that includes” in claim 4 and “that comprises the steps of” in claim 8 is non-standard and somewhat confusing. Examiner recommends replacing this language with the clearer phrasing “The method of claim 1 further comprising” in both claim 4 and claim 8.
Claim Rejections - 35 USC § 112(a)
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 1-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The claimed invention in independent claim 1 is directed to a method of determining whether a patient who experienced a MI has or is at risk of having adverse post-ischemic cardiac remodeling and treating the patient. The method of the independent claim comprises determining the level of GDF3 in a sample obtained from the patient and administering a therapeutically effective amount of a GDF3 inhibitor to a subject identified as having high levels of GDF3.
Claim 1 encompasses the use of any type of sample obtained from a subject. Claim 2 limits the sample type to a blood sample.
Claim 3 indicates that level of GDF3 is determined 1-15 days after MI.
Claim 4 recites contacting the sample with any agent that selectively binds to the GDF3 protein.
Claim 13 indicates that the agent of claim 4 binds selectively to a mature domain of GDF3 protein.
The claimed invention in independent claim 9 is directed to a method of treating adverse post-ischemic cardiac remodeling in a patient who experienced a MI comprising administering a therapeutically effective amount of a GDF3 inhibitor.
Claims 10-12 further limit the type of GDF3 inhibitor (anti-GDF3 neutralizing antibody, claim 10) and its specific binding behavior (claims 11-12).
Regarding treatment of the subject with a GDF3 inhibitor (as recited in independent claims 1 and 9), the general administration of treatment is minimally supported by basic recitation in the specification (see, e.g. Pg. 9, 14 which recite administering a GDF3 inhibitor to a patient), however the specification does not provide any data or reduction to practice that indicates that the inventor had actually performed or actually had possession of this step of the method at the time of filing. The specification does not indicate that the inventor has performed or reduced to practice this method of treatment with any particular GDF3 inhibitor. The specification does not provide evidence that supports the recited treatment step for the specific condition claimed in the methods.
Regarding predictability in the prior art, the prior art contains some teachings relevant to the use of a GDF3 inhibitor for the treatment of adverse post-ischemic cardiac remodeling, as evidenced by Li et al (US 2020/0087367 A1) (Par. 7, 12, 79-80, 121; Claims 1 and 15-17). These teachings comprise some reduction to practice of treatment with a GDF3 inhibitor, however reduction to practice is limited to specific species of GDF3 inhibitor, and in the teachings of the prior art, administration of treatment is not specifically tied to level of GDF3 in a sample (as in instant claim 1). There is no specific or explicit reduction to practice of the particular GDF3 inhibitors recited in claims 10-12 in a treatment method such as the one claimed. Thus, predictability in the art for the method of treatment as claimed is low, and the specification provides no reduction to practice for the method of treatment as claimed. As such, the contents of the disclosure and the prior art are insufficient to indicate to one of ordinary skill in the art that the inventor had possession of the full scope of the claimed invention at the time of filing.
Regarding claims 10-13, these claim a genus of GDF3 inhibitors and binding agents by their desired function (i.e. “anti-GDF3 neutralizing” or by specific binding function, as in claims 12-13). Claiming the inhibitor or agent by its function as an anti-GDF3 neutralizing antibody is insufficient because it is not clear what particular structural elements make an anti-GDF3 neutralizing antibody distinct from a generic antibody that binds to GDF3. Though one might be able to identify the functional output of such an antibody, the specific structure associated with that output is not clear and is not defined by the instant disclosure. Similarly, regarding the functional limitations on the specific binding behavior of the recited antibody/agent (as in claims 11-13), the disclosure does not provide description of a particular structural feature that imparts the claimed antibodies with their particular claimed function. Rather, the specification only describes the structure of the antigen to which the claimed genera of antibodies bind without describing the structure of the antibody that is responsible for imparting the critical binding function. This problem is particularly relevant to claim 13 which is not even limited to the generic structure of an antibody, and instead encompasses any species of binding agent that fulfills the recited function.
Further, as discussed in the treatment section above, there is no reduction to practice which demonstrates administering any of these particular antibodies as a GDF3 inhibiting treatment (claims 10-12), or that demonstrates use of the agent of claim 13 in the described method for detection of GDF3 levels. Regarding claims 10-12, the specification provides no reduction to practice for the treatment step. Regarding claim 13, the specification provides some reduction to practice for the use of an agent that selectively binds to GDF3 protein (see antibodies recited in the examples of Pg. 22-26) but does not provide detail as to whether or not the antibodies used in the examples selectively bind to a mature domain of GDF3 protein. The specification provides literal support for the recited binding functions (Pg. 10), but does not describe the particular structure of any particular antibody or binding agent that meets these limitations (i.e. no specific species of commercially available antibody is described, no sequences or structural description of an antibody synthesized by the inventor is provided).
The specification does not identify any partial structure or other identifying characteristics that are responsible for imparting the claimed functions and binding functions. The specification fails to disclose, for example, what particular amino acid residues of the antibodies are responsible for conferring the desired functional properties. Describing the structure of the epitope or antigen bound is insufficient to describe the antibodies or binding agents themselves, since there is no structure-function correlation either disclosed or known in the art (as discussed below, antibody sequence does not correlate to binding in a predictable fashion). Accordingly, the limited disclosure of antibodies and binding agents in the instant specification is not sufficient to reflect the breadth and variation within the instantly claimed genera. A skilled artisan cannot, as one can do with a fully described genus, visualized or recognize the identity of the members of the genus that would exhibit the claimed functional properties. The structural features common to the members of the genus are unknown.
Additionally, there is a general lack of structure-function correlation for the claimed antibodies and binding agents. The general structure of antibodies was known in the art before the effective filing date, and it was known that the complementarity determining regions (CDRs) of antibodies generally control antigen binding. While CDRs are necessary for binding, they are highly diverse in structure, and their sequences do not correlate to binding in a predictable fashion. See for instance:
Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response,” The Journal of Immunology (2004), 173(12):7358-7367), who made three antibodies that bind to the same 12-mer but have very different CDRs.
Lloyd et al. (“Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens,” Protein Engineering, Design & Selection (2009), 22(3):159-168) found that on average, about 120 different antibodies in a library can bind to a given antigen.
Edwards et al. (“The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BlyS,” Journal of Molecular Biology (2003), 334:103-118) found that a library contained over 1000 antibodies that bound to a single 51 kDa protein, including 1098 unique VH and 705 VL sequences. There were 568 different CDR3 regions, indicative of high diversity.
These references indicate that there was no art-recognized correlation between the structure of an antibody or binding agent and its binding properties. A single antigen can be bound by a very large and structurally diverse genus of antibodies and binding agents. There is no common structural relationship even for antibodies or binding agents that bind to the same protein sequence or even to the same epitope. Although the specification discloses specific antibodies that perform the claimed binding functions, the specification does not describe the structural characteristics common to the genus of antibodies that bind the claimed genus of epitopes. The specification does not provide guidance as to what essential structures of antibodies or binding agents would confer the necessary claimed functions and does not allow one of ordinary skill in the art to visualize or recognize the members of the genus of antibodies or binding agents that would be able to achieve the claimed functions.
Dependent claims 2-8 and 10-13 are rejected because they depend from a rejected claim and fail to remedy its deficiencies.
Claims 1, 3-8 and 13 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 determination of cardiac remodeling in a patient based on a determined level of GDF3 in a blood sample obtained from the patient, does not reasonably provide enablement for determination of cardiac remodeling in a patient based on a determined level of GDF3 in any type of sample obtained from a patient at any time point (i.e. those recited in claim 3). 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 or use the invention commensurate in scope with these claims.
A determination of enablement involves the consideration of the following factors: the breadth of the claims; the nature of the invention; the state of the prior art; level of one or ordinary skill; level of predictability in the art; amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding the breadth of the claims and the nature of the invention: The claims are directed to a method of determining and treating adverse post-ischemic cardiac remodeling in a patient based on the level of GDF3 in a sample obtained from the patient. The independent claim does not establish any particularly defined relationship between GDF3 levels and the presence or risk of post-ischemic cardiac remodeling. Claims 1, 3-8, and 13 encompass determination of GDF3 level in any sample type. Claim 3 specifically recites the method wherein the level of GDF3 is determined between 1 and 15 days after myocardial infarction
Regarding the state of the prior art, the level of one of ordinary skill, and the level of predictability in the art: The level of predictability in the art for the method as claimed is low, as no prior art was found which specifically correlates a determined level of GDF3 in a sample to risk, presence or treatment of post-ischemic cardiac remodeling. As such, there is no predictable or art-recognized relationship between GDF3 levels in a sample from a patient and the presence or risk of adverse post-ischemic cardiac remodeling. No prior art was found which particularly defined or determined GDF3 levels in patients after myocardial infarction. The state of the prior art indicates that GDF3 is present in certain sample types, but does not indicate that GDF3 is present in all sample types, and does not support the assertion that a correlation between GDF3 and adverse post-ischemic cardiac remodeling which is observed in the blood samples from patients within 7 days after MI would be conserved across all sample types and time points encompassed by the instant claims. For example no prior art was found that supports or determines the presence of GDF3 in samples such as urine, mucus, saliva, semen, fecal matter, sputum, etc. or which indicates a correlation between GDF3 in these sample types and the presence or risk of adverse post-ischemic cardiac remodeling. See for example:
Chen at el (The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo. Development. 2006 Jan;133(2):319-29.)
Hexige et al (Expression pattern of growth/differentiation factor 3 in human and murine cerebral cortex, hippocampus as well as cerebellum. Neurosci Lett. 2005 Dec 2;389(2):83-7.)
Which discuss the presence of GDF3 in bone during embryonic development, and the presence of GDF3 in brain, thymus, spleen, bone marrow, and adipose tissue samples in adults.
Regarding amount of direction provided by the inventor and the existence of working examples: Regarding sample type and timing of GDF3 determination (wherein claims 1, 3-8, and 13 encompass the use of any sample type in the method, wherein claim 3 indicates a time period of 1-15 days post MI), the instant specification only includes description and reduction to practice of GDF3 measured in mouse and human samples, wherein the sample type is either a blood sample or a cardiac tissue sample (Pg. 22-26). The data and reduction to practice provided in the specification regarding timing shows an increase in secreted GDF3 protein level in the plasma of MI mice from day 0 to day 2 and a decrease thereafter until day 7 after MI (Pg. 25); GDF3 expression is also analyzed in excised mouse hearts 7 days after MI (Pg. 25), and human plasma samples at day 4 post MI (Pg. 26); no other data or reduction to practice is provided for other sample types or time points or combinations thereof. The specification provides no reduction to practice or data for levels of GDF3 measured more than 7 days after MI.
Regarding quantity of experimentation: quantity of experimentation is considered undue because neither the prior art nor the instant specification provides support which would lead one of ordinary skill in the art to conclude that trends observed in the limited reduction to practice (i.e. correlation between GDF3 levels and adverse post-ischemic cardiac remodeling would be conserved across the scope of all sample types and time points that are encompassed by the claims.
Dependent claims 3-8 and 13 are rejected because they depend from a rejected claim and fail to remedy its deficiencies.
Claim Rejections - 35 USC § 112(b)
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 1-13 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.
Claim 1 is vague regarding “the level of GDF3”. There is no prior introduction of “a level of GDF3” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 1 is rejected as indefinite because it references measurements made in a sample obtained from a “patient” but then subsequently references administering treatment to a “subject” wherein it is unclear whether the terms “patient” and “subject” refer to the same entity. Clarification is required.
Claim 1 is rejected as indefinite over the recitation “a subject identified as having high levels of GDF3”. The term “high levels” is a relative term which renders the claim indefinite. The term “high levels” 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. As such, one of ordinary skill in the art cannot reasonably determine the metes and bounds of this limitation and cannot definitively determine whether or not levels of GDF3 are at an appropriate level to require administration of treatment. Though the specification at Pg. 6-7 provides some definition for the terms high and low, the definition provided is not sufficient to make the term definite because the description presents multiple different possibilities and standards for determining and defining high and low
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “the sample is a blood sample”, and the claim also recites “more particularly a serum sample” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For the purposes of applying prior art in the present office action, any kind of blood sample is understood to read on this limitation of the instant claim, since this appears to be the broadest reasonable interpretation of the claim language.
Claim 4 is vague regarding “the GDF3 protein”. There is no prior introduction of “a GDF3 protein” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
The terms “high levels”, “low levels” as well as reference to “high” and “low” probabilities in claim 7 are relative terms which render the claim indefinite. The terms are 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. As such, one of ordinary skill in the art cannot reasonable determine the metes and bounds of these limitations and cannot definitively determine the boundaries that define a low and high level of GDF3 or a low and high probability that a patient has or is at risk of having adverse post ischemic cardiac remodeling. Though the specification at Pg. 6-7 provides some definition for the terms high and low, the definition provided is not sufficient to make the terms definite, because the description presents multiple different possibilities and standards for determining and defining high and low.
Claim 8 is vague regarding “the steps of” there is no prior introduction of “steps” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 8 is indefinite because it recites comparing quantified levels of GDF3 to a reference value to make diagnostic or prognostic conclusions, but the predetermined reference value is not defined or described. It is therefore not clear what the predetermined reference value is or represents or what particular predetermined reference values are suitable for use in the method as claimed.
Claim 8 is vague regarding “the content”. There is no prior introduction of “a content” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 9 is vague regarding “the subject”. There is no prior introduction of “a subject” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 11 is vague regarding “the mature domain of GDF3”. There is no prior introduction of “a mature domain of GDF3” in the claims, therefore there is insufficient antecedent basis for this limitation in the claims.
Claim 12 is vague regarding “the amino acid sequence” and “the amino acid residue”. There is no prior introduction of “an amino acid sequence” or “an amino acid residue” in the claims, therefore there is insufficient antecedent basis for these limitations in the claims.
Claim 12 is rejected as indefinite over the phrasing “the anti-GDF3 neutralizing antibody binds to the amino acid sequence that ranges from the amino acid residue at position 251 to the amino acid residue at position 364 in SEQ ID NO: 1”. This recitation is indefinite because it is unclear whether this is intended to indicate that the antibody must bind to all of the amino acid residues within the recited range or whether it only needs to bind to some (i.e. one or more) of the amino acid residues within the recited range (i.e. an epitope within the recited range). For the purposes of applying prior art in the present office action, this limitation is interpreted to only require that the antibody binds to some of the amino acid residues within the recited range (i.e. an epitope within the recited range), as this appears to be the broadest reasonable interpretation of the claim language. Clarification is required.
Dependent claims 2-8 and 10-13 are rejected as indefinite because they depend from an indefinite claim and fail to remedy its deficiencies.
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 1-8 and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Claims 1-8 and 13 are directed to a method of determining whether a patient who experienced a MI has or is at risk of having adverse post-ischemic cardiac remodeling and treating the patient. This method therefore comprises two judicial exceptions, a law of nature (i.e. the naturally occurring correlation between levels of expression of a particular biomarker and a particular disease state, in this case the correlation between GDF3 and adverse post-ischemic cardiac remodeling) and an abstract idea (i.e. the process of using GDF3 expression data to draw a conclusion about disease state or risk is a mental process which can be performed in the human mind).
Similar concepts have been held by the courts to constitute law of nature/natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics LLC, 859, F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), and the natural relationship between a patient’s CYP2D6 metabolizer genotype and the risk that the patient will suffer QTc prolongation after administration of iloperidone in Vanda Pharmaceuticals Inc v. West-Ward Pharmaceuticals, 887 F.3d 1117, 1135-36, 126 USPQ2d 1266, 1281 (Fed. Cir. 2018). (See MPEP 2106.04(b)).
The correlation is naturally occurring and is a judicial exception because it exists in principle apart from any human action. The correlation itself therefore cannot form the basis of eligibility.
As such, the predicting and detecting of adverse post-ischemic cardiac remodeling to which the claims are directed is itself a judicial exception which cannot form the basis of eligibility and cannot integrate the judicial exceptions into a practical application because they are directed to the performance of the judicial exception itself.
Regarding integration of the judicial exceptions into a practical application, applicant has attempted to integrate the judicial exceptions into a method of treatment. Regarding whether integration of the judicial exception into a method of treatment comprises integration of the judicial exception into a practical application, MPEP 2106.04(d)(2) provides the following: “One way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. The application or use of the judicial exception in this manner meaningfully limits the claim by going beyond generally linking the use of the judicial exception to a particular technological environment, and thus transforms a claim into patent-eligible subject matter. Such claims are eligible at Step 2A, because they are not “directed to” the recited judicial exception”. Regarding the particularity of the treatment step, the MPEP indicates that recitation of an abstract idea in conjunction with a step of, for example, “administering a suitable medication to a patient” does not integrate the judicial exception into a practical application because the treatment step is general (not particular) and is merely instruction to “apply” the judicial exception in a generic way.
As it applies to the instant case, the claimed treatment step recites “administering a therapeutically effective amount of a GDF3 inhibitor to a subject identified as having high levels of GDF3”. This does not constitute a particular treatment step. The claim indicates that a particular population of subjects should receive treatment (i.e. those with high levels of GDF3) but does not provide detail which allows one of ordinary skill in the art to determine whether or not a given subject falls into the treatment population (i.e. what constitutes a high level of GDF3 is relative and not defined). As such, the treatment step is not clear or particular and does not serve to integrate the judicial exceptions into a practical application, because it is unclear exactly how and to whom the treatment step is applied or how it relates to or integrates the particular judicial exceptions.
Limitations recited in the dependent claims further limit the sample type and timepoint and the reagents and methods used to evaluate GDF3 levels, but these do not render the treatment step sufficiently particular and do not themselves integrate the judicial exceptions into a practical application. The limitations recited in dependent claims 7 and 8 are themselves judicial exceptions in that they comprise comparing data and drawing prognostic and diagnostic conclusions (i.e. mental steps), and further these limitations are not tied into the treatment step itself or any other kind of practical application.
The claims do not include additional elements that are sufficient to amount to significantly more than the recited judicial exceptions. Additional elements of the claims which are not themselves directed to judicial exceptions comprise determination of GDF3 levels in a sample, and administration of GDF3 inhibitor as a treatment. The step of administering treatment is recited at a high level of generality using therapeutics which are known in the art, as demonstrated by Li et al (US 2020/0087367 A1). Further the generality of the treatment step is such that it constitutes mere instructions to apply the judicial exception, which is not sufficient to constitute significantly more than the judicial exceptions, as further discussed in MPEP 2106.05(f). The steps determining GDF3 levels in a sample obtained from a patient comprises mere data gathering for the performance of the judicial exception, since the determination of disease state is based on biomarker quantity in the sample. Additionally, the quantification of biomarkers is recited at a high level of generality, and detection of biomarkers in a biological sample by any means is specifically recognized by the MPEP as routine and conventional activity in the life science arts, as discussed in MPEP 2106.05(d).
Additionally, the determination of GDF3 levels in a biological sample from a subject is routine and conventional in the art, as demonstrated by the teachings of the prior art. For example, Wang et al (GDF3 Protects Mice against Sepsis-Induced Cardiac Dysfunction and Mortality by Suppression of Macrophage Pro-Inflammatory Phenotype. Cells. 2020; 9(1):120.) discloses measurement of GDF3 in serum by a commercially available ELISA, demonstrating that detection of GDF3 in biological samples was performed by methods which are routine and conventional in the art with reagents which are known and commercially available.
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.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li et al (US 2020/0087367 A1).
The preamble of claim 9 recites “a method of treating adverse post-ischemic cardiac remodeling in a patient who experienced a myocardial infarction comprising”. A preamble is generally not accorded any patentable weight in a case such as this where it merely recites the purpose of a process or the intended use of a structure and where the body of the claim does not depend on the preamble for completeness, but instead the process steps are able to stand alone (MPEP 2111.02). The recitation of the method as for “treating adverse post-ischemic cardiac remodeling” is at best directed to the intended purpose of the claim, and does not further limit the steps of the method themselves. The body of the method does not refer back to the particular condition being treated or to the particular “patient” of the preamble, but rather recites administering a treatment to a subject. As such, the body of the method is understood to stand on its own while the preamble is understood to set forth the intended use of the method. Therefore, prior art which teaches administering to a subject a therapeutically effective amount of a GDF3 inhibitor is understood to be sufficient to meet the instant claim, regardless of whether the prior art teaches the specific limitations and intended use of the preamble.
However, limitations of the preamble are addressed in the rejection below for the purpose of compact prosecution.
Regarding claim 9, Li teaches a method comprising administering to a subject a therapeutically effective amount of a GDF3 inhibitor, wherein the subject has experienced a myocardial infarction and wherein the treatment may address post-ischemic cardiac remodeling in the subject; namely, Li discloses use of an antigen of GDF3 (an ActRII polypeptide) as a potential treatment for cardiac remodelling, heart failure, or another complication of heart failure that may occur after myocardial infarction (Par. 7, 12, 79-80, 121; Claims 1 and 15-17).
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.
Claims 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (US 2020/0087367 A1), as applied to claim 9 above, and further in view of Arslan et al (WO 2012/057613 A1; IDS entered) and Knopf et al (WO 2006/002387 A2; IDS entered)
Regarding claims 10-12, Li teaches the method of claim 9, as described above, but does not explicitly teach the method wherein the GDF3 inhibitor is an anti-GDF3 neutralizing antibody.
Regarding claims 10-12, Arslan teaches that the use of neutralizing antibodies as therapeutic inhibitors is known in the art, and discloses the use of a neutralizing antibody to prevent or treat cardiac remodeling after MI (Pg. 3, Ln. 8-10, 23-25).
Regarding claims 10-12, Knopf discloses use of an antibody that binds specifically to a mature GDF3 peptide for the purpose of antagonizing (i.e. inhibiting) its activity (Pg. 3, Ln. 7-8; Pg. 26, Ln. 9-13). Knopf further discloses the amino acid sequence of instant SEQ ID NO: 1 (Knopf, SEQ ID NO: 3, Fig. 3), such that the anti-GDF3 antibody disclosed by Knopf for neutralizing and inhibiting GDF3 by binding to a mature peptide is understood to fulfill the limitations of the antibody recited in claims 10-12.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li to include the use of an anti-GDF3 neutralizing antibody as the GDF3 inhibitor. Li teaches that inhibition of GDF3 is useful in the treatment of heart failure and cardiac remodeling after MI, while Arslan teaches that neutralizing antibodies are useful therapeutics for preventing and treating cardiac remodeling after MI. Arslan discloses a specific species of anti-GDF3 antibody that binds to a mature peptide and inhibits/neutralizes the activity of GDF3. As such, one of ordinary skill in the art would recognize that an anti-GDF3 neutralizing antibody such as the one taught by Knopf would serve the functionally equivalent purpose of GDF3 inhibition, such that substitution of an anti-GDF3 neutralizing antibody for the GDF3 inhibitor taught by Li amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success.
Subject Matter Free of Prior Art
Claims 1-8 and 13 are rejected as described above, but (as best interpreted in light of the 112(b) issues noted above) contain subject matter which appears to be free of the prior art.
The closest prior art is Li et al (US 2020/0087367 A1), which teaches administration of a GDF3 inhibitor as treatment for adverse post-ischemic cardiac remodeling after MI (Par. 7, 12, 79-80, 121; Claims 1 and 15-17).
Li differs from the instant claim in that it does not teach determining levels of GDF3 in a sample obtained from the patient, and does not teach that administration of treatment is related to the level of GDF3 in the patient sample.
No prior art was found which discloses a method of determining whether a patient who experienced a MI has or is at risk of having post-ischemic cardiac remodeling by determining the level of GDF3 in a sample from a patient.
Conclusion
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677