DETAILED ACTION
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 without traverse of Group I in the reply filed on 7/10/26 is acknowledged.
Claim Status
Claims 1, 82-83, 86, 92, 94-96, 98-99, 102, 104, 106, 108, 110-111, 128, 130-131, and 145 are pending.
Claims 111, 128, 130-131, and 145 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Claims 102, 104, 106, and 108 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/10/26.
Claims 1, 82-83, 86, 92, 94-96, 98-99, and 110 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 10/5/23, 4/3/24, 2/14/25, 8/27/25, and 7/10/26 have been considered. Signed copies are enclosed.
The references lined through were not considered because a copy of the reference was not provided (see 37 CFR 1.98(a) ) and/or a concise English statement of relevance was not provided (See 37 CFR 1.98(a) and MPEP 609.04(a)).
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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.
Written Description
Claims 1, 82-83, 86, 92, 94-96, 98-99, and 110 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 “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a method for treating a subject with caveolin-1 peptide therapy wherein the subject is suffering from fibrosis, the method comprising the steps of obtaining or having obtained a biological sample from the subject, treating or having treated a cell of the biological sample with caveolin-1 peptide or derivative thereof, measuring expression level of a biomarker in the cell, and comparing the expression level of the biomarker to a control sample. The claim recites “caveolin-1 peptide or derivative thereof.” This component of the method is not adequately described, and therefore the claimed method is not adequately described.
The instant specification defines native caveolin-1 as having 178 amino acids and being represented by SEQ ID NO:1. However, the claims are not limited to SEQ ID NO:1, and the term “caveolin-1 peptide or derivative thereof” is not defined in the specification. The claims require that the caveolin-1 peptide or derivative thereof have a specific function of treating all types of fibrosis, which have unique etiology and pathology. The specification does not provide a structure that correlates with the required function. The specification does not define any structures that would include a peptide as a “derivative.” Further, the specification presents a series of highly related peptides as species of caveolin peptides but these highly similar peptides are not representative of the highly variable caveolin-1 peptide and derivative thereof genus, which due to the lack of definition for the terms “caveolin-1 peptide” and “derivative,” could potentially encompass completely different polypeptides that do not share a common structure.
The specification discloses SEQ ID NO:1-110, as having the required functions. However, the claim encompasses any protein that could fall within the undefined genus of “caveolin-1 peptide or derivative thereof.” The specification provides no definition for acceptable derivation of the caveolin peptide. These peptides have no correlation between their structure and function. The specification provides no guidance regarding which caveolin-1 peptides or derivatives thereof are capable of the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of SEQ ID NO:1-110, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional caveolin-1 peptides and derivatives thereof that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of caveolin-1 peptides and derivatives thereof encompassed by the instant claims (see e.g. page 661, left column).
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of a representative number of species across the breadth of the genus, one of skill in the art would reasonably conclude that only the enumerated sequences provided for species of caveolin-1 peptides and derivatives, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a).
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
Claims 1, 82-83, 86, 92, 94-96, 98-99, and 110 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 treating idiopathic pulmonary fibrosis (IPF) with CSP7, does not reasonably provide enablement for treating any fibrosis except IPF with any caveolin-1 peptide or derivative thereof except CSP7. 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.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
1) nature of the invention; 2) the breadth of the claims;
The instant claims are drawn to a method for treating a subject with caveolin-1 peptide therapy wherein the subject is suffering from fibrosis, the method comprising the steps of obtaining or having obtained a biological sample from the subject, treating or having treated a cell of the biological sample with caveolin-1 peptide or derivative thereof, measuring expression level of a biomarker in the cell, and comparing the expression level of the biomarker to a control sample. The claim encompasses the overly broad genus of “caveolin-1 peptide[s] or derivative[s] thereof.”
The instant specification defines native caveolin-1 as having 178 amino acids and being represented by SEQ ID NO:1. However, the claims are not limited to SEQ ID NO:1, and the term “caveolin-1 peptide or derivative thereof” is not defined in the specification. The claims require that the caveolin-1 peptide or derivative thereof have a specific function of treating all types of fibrosis, which have unique etiology and pathology. The specification does not define any structures that would include a peptide as a “derivative.” Further, the specification presents a series of highly related peptides as species of caveolin peptides but these highly similar peptides are not representative of a highly variable genus, which due to the lack of definition for the terms “caveolin-1 peptide” and “derivative,” could potentially encompass completely different polypeptides that do not share any common structure. Therefore, the genus of “caveolin-1 peptide and derivative thereof” is overly broad.
Further, the “caveolin-1 peptide and derivative thereof” must treat an overly broad genus of disorders encompassed by the term “suffering from fibrosis” and “predicting or determining efficacy.” The instant specification does not provide a definitive list of disorders, but instead describes exemplary fibrotic diseases including interstitial lung disease, liver fibrosis, renal fibrosis, skin fibrosis, glomerulonephritis, systemic sclerosis, cardiac fibrosis, myocardial fibrosis, kidney fibrosis, hepatic cirrhosis, renal sclerosis, arteriosclerosis, macular degeneration, ocular scarring, cataracts, retinal and vitreal retinopathy, Grave's ophthalmopathy, neurofibromatosis, scleroderma, glioblastoma, keloids and hypertrophic scarring, peritoneal fibrotic disease, chronic obstructive pulmonary disease, post- operative fibroids, diabetic nephropathy, gynecological cancer, myeloproliferative syndrome, myeloid leukemia, myelodysplastic syndrome, inflammatory bowel disease, non-alcoholic fatty liver disease, fibrosarcoma, rheumatoid arthritis, non-alcoholic steatohepatitis, Alport syndrome, or chronic COVID syndrome.
The interstitial lung disease can include exemplary diseases idiopathic pulmonary fibrosis, lymphangioleiomyomatosis, nonspecific interstitial pneumonia, idiopathic interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, pulmonary sarcoidosis, diffuse alveolar damage, systemic sclerosis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, drug-induced interstitial lung disease, or occupational interstitial lung disease.
However, neither the specification nor the claims are limited to only these example disorders. Any disorder that results in fibrosis is encompassed. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The encompassed disorders are highly heterogeneous at both the molecular and clinical level. The breadth of the encompassed genus of disorders, when combined with the overly broad genus of caveolin-1 peptides and derivatives thereof, at least some of which may not have been discovered, would require undue experimentation to practice the claimed invention.
3) the state of the prior art; 5) the level of predictability in the art;
The state of the art with regard to broadly treating all fibrotic disorders is underdeveloped. In particular, there is no known agent that is effective against all fibrotic disorders. The fibrosis disease art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all fibrotic diseases in a subject, with the claimed genus of caveolin-1 peptides and derivatives thereof makes practicing the claimed invention unpredictable.
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
In addition, predicting the success of a treatment for fibrotic disease is unpredictable and presents challenges beyond initial screening. For example, Nair et al (Sci 2026, 8(1), 9; https://doi.org/10.3390/sci8010009) teaches that liver fibrosis represents the final common pathological response to chronic hepatic injury originating from diverse etiologies, including viral hepatitis, alcoholic liver disease (ALD), and metabolic dysfunction-associated steatohepatitis (MASH) (see e.g. abstract). It is characterized by an excessive deposition of extracellular matrix, which disrupts the architecture of the liver and can lead to cirrhosis, liver failure, and hepatocellular carcinoma (see e.g. abstract). Despite its significant clinical impact, early detection of liver fibrosis is still limited due to insufficient diagnostic technologies and low public awareness (see e.g. abstract). Currently, liver transplantation is the only definitive treatment, but it is limited by donor shortages and the need for lifelong immunosuppression (see e.g. abstract). Recognizing the cellular heterogeneity within the hepatic fibrogenic compartment is critical for understanding fibrosis progression and therapeutic targeting (see e.g. page 3, first paragraph). This diversity in cellular origin underscores a key challenge for therapeutic strategies as alternative sources could sustain fibrogenesis and limit treatment efficacy (see e.g. page 3, first paragraph). Despite the increasing understanding of the mechanisms behind fibrogenesis and fibrosis regression, the translation of potential antifibrotic treatments into approved therapies continues to face challenges due to ongoing issues with disease modeling, diagnostic accuracy, and regulatory compliance (see e.g. section 3.4, page 7). These obstacles impede the prioritization of compounds, the design of clinical studies, and the validation of biomarkers, particularly in the case of MASH-related fibrosis (see e.g. section 3.4, page 7).
Glass et al (ClinRespirJ.2022;16:84–96) teaches that etiopathogenesis of IPF is not fully understood, and treatment options are limited (see e.g. abstract). Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells (see e.g. abstract). The mainstay therapies are the oral antifibrotic drug spirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression (see e.g. abstract). Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy (see e.g. abstract). Predicting the clinical course of IPF based on respiratory function and radiologic imaging is unreliable and, at this time, we cannot predict disease trajectory accurately (see e.g. page 90, right column, section 7).
Granata et al (Journal of Translational Medicine (2026) 24:346) teach that chronic kidney disease (CKD) is estimated that by 2040, it will be the 5th highest cause of years of life lost globally due to the aging population and the rising prevalence of age-related diseases such as hypertension and diabetes (see e.g. abstract). Although kidney transplantation remains the gold standard therapy for this condition, the limited availability of donor organs restricts access to only a minority of patients (see e.g. page 16, left column, second to last paragraph). Although pre-clinical studies in animal models have reported promising results, their application in clinical studies involving humans is scarce or lacking (see e.g. page 16, left column last paragraph to right column, first paragraph). Despite the numerous progresses into the comprehension of the molecular mechanisms underlying kidney fibrosis, the therapeutic options currently available remain very limited and are mainly focused on slowing the progression of the disease rather than reversing the fibrotic process (see e.g. page 7, left column, “Emerging therapeutics for kidney fibrosis” section).
While the above references demonstrate the extremely unpredictable nature of treatment of various fibrotic disorders, it is important to remember that the claims are even broader than the three diseases identified in the references, and includes a very large number of otherwise unrelated disorders. Given the extremely broad nature of the encompassed diseases, which have variable etiology and pathology, and the teachings of Nair, Glass, and Granata, one of skill in the art would not be able to predict the effectiveness of the encompassed broad and undefined genera of caveolin-1 peptides and derivatives thereof in each of the claimed fibrotic diseases.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification provides several examples using tissues including precision cut lung slices (PCLS) and lung fibroblasts or macrophages, taken from patients with IPF to measure biomarkers after exposing the samples to CSP-7 (see instant Examples 2-5, 7, and 9-10). Example 6 and 8 describes a study in mice that were administered bleomycin as a model for idiopathic pulmonary fibrosis, and then treated with CSP-7 or control peptide. The studies show SMAD, phospho-SMAD, galectin-7, and IL-11 in lung tissue homogenates or bronchoalveolar lavage fluid. However, these examples do not show the steps of either of the claimed methods. In particular, none of the methods of the examples from the specification show selection of a subject for administration of any caveolin-1 peptide or derivative after measurement of a biomarker and comparison to control. Therefore, one of skill in the art would be left to identify a caveolin-1 peptide or derivative, then match the selected peptide or derivative to a selected fibrotic disorder, then identify biomarkers that could identify a patient for treatment, or identify efficacy of the treatment. This level of experimentation would be undue for one of ordinary skill in the art.
In conclusion, the claimed invention does not provide enablement for treatment of all fibrotic disorders with all of the encompassed caveolin-1 peptides or derivatives thereof. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
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, 82-83, 86, 92, 94-96, 98-99, and 110 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 recites “obtained or having obtained” and “treating or having treated”, which render the claim indefinite. The phrases indicate a step in a method, or a past event. It is unclear if the past event is included in the method steps, or if the step of obtaining a sample is separate from the method.
Claim 1 recites “caveolin-1 peptide or derivative thereof.” The instant specification does not define either “caveolin-1 peptide” or “derivative.” The specification identifies native caveolin-1 as SEQ ID NO, but does not define the metes and bounds of the peptide genus that would qualify as a “caveolin-1 peptide.” Further, the specification does not set forth criteria for identifying the “derivative” molecules. Therefore, the scope of the genus encompassing the “caveolin-1 peptide and derivative thereof” is indefinite.
Claims 1 and 99 recite both that “if expression level of …CALR…is increased, then administering caveolin-1 peptide or derivative thereof to the subject” and “if expression level of …CALR…is decreased, then administering caveolin-1 peptide or derivative thereof to the subject.” It is unclear how the measurement of increase and decrease could both be indicative of administration.
In claim 95, the phrases “retinal and vitreal” and keloids and hypertrophic scarring” render the claim indefinite. It is unclear if the terms represent alternative choices within the Markush grouping, or if both types of fibrosis must be present at the same time.
The term “internal control” in claim 98 is a relative term which renders the claim indefinite. The term “internal control” 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.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
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 82-83, 86, 92, 94-96, 98-99, and 110 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106. The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention. The instant claims recite a method of predicting or determining the efficacy of a caveolin-1 peptide or derivative thereof, the method comprising treating a biological sample from a subject with fibrosis with the caveolin-1 peptide or derivative thereof, wherein the biological sample is treated ex vivo or in vitro, measuring an expression level of a biomarker in the biological sample from the subject, and comparing the biomarker expression level to a control sample. The claim is directed to a method, which is a statutory category of invention.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claim as a whole, the instant claims are determined to be directed to a law of nature/natural principle and an abstract idea. The relationship between the recited biomarkers and efficacy of treatment with caveolin-1 peptide or derivative thereof is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular response to treatment for natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). The use of the biomarkers and correlation with disease could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
Third, a claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The claims identifies sample types (e.g. cell types) for testing and subjects to be tested, and the specification identifies well-known assays for determining protein product expression levels, such as western blot, mass spectrometry, flow cytometry, and other conventional assays (see instant specification paragraph [0018]. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in blood by any means has been determined as one of the well-understood, routine, conventional activity: see Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017). Regarding the assays to detect protein expression products, the assays claimed are routine in the art for measuring protein expression. This is acknowledged by the instant specification, which states that "The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized enzyme-linked immunosorbent assay.” (see paragraph [0072]). Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities. This is also supported by the findings of the in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. v. Prometheus Labs., Inc., 566 U.S. _, 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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(s) 1, 82-83, 86, 92, 94-96, 98-99, and 110 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Marudamuthu et al ("Caveolin-1-derived peptide limits development of pulmonary fibrosis," Sci. Transl. Med. 11, eaat2848 (2019); hereinafter "Marudamuthu").
Instant claim 1 is directed to a method for treating a subject with caveolin-1 peptide therapy, wherein the subject is suffering from fibrosis, the method comprising the steps of:(a) obtaining or having obtained a biological sample from the subject;(b) treating or having treated a cell of the biological sample with a caveolin-1 peptide or derivative thereof;(c) measuring an expression level of a biomarker in the cell; and(d) comparing the expression level of the biomarker to a control sample; wherein the biomarker is myeloid-derived growth factor (MYDGF), soluble RAGE, phosphorylated mothers against decapentaplegic homolog 2/3 (pSMAD2/3), platelet-derived growth factor receptor beta (PDGFRP), galectin-7 (LGALS7), interleukin-11 (IL-11), matrix metalloproteinase-2 (MMP-2), chemokine ligand 7 (CXCL-7), soluble CD 163, phosphorylated mTOR (p-mTOR), phosphorylated PDGFRP (pPDGFRP), prolifin (PROF 1), calmodulin 2 (CALM2), calreticulin (CALR), peptidyl-prolyl cis-trans isomerase A (PPIA), or eukaryotic translation initiation factor 5A (EIF5A1); and if the expression level of MYDGF, PROF 1, CALM2, CALR, PPIA, IF5A1, LGALS7, soluble RAGE, or EIF5A1 is increased, then administering caveolin-1 peptide or derivative thereof to the subject; or if the expression level of PDGFRP, pPDGFRP, p-mTOR, CALR, IL-11, MMP-2, CXCL7, soluble CD 163, or pSMAD2/3 is decreased, then administering caveolin-1 peptide or derivative thereof to the subject.
Instant claim 82 is directed to a method of predicting or determining the efficacy of a caveolin-1 peptide or derivative thereof, the method comprising:(a) treating a biological sample from a subject with fibrosis with the caveolin-1 peptide or derivative thereof, wherein the biological sample is treated ex vivo or in vitro;(b) measuring an expression level of a biomarker in the biological sample from the subject; wherein the biomarker is MYDGF, soluble RAGE, pSMAD2/3, PDGFR3, pPDGFR3, LGALS7, IL-11, MMP-2, CXCL7, sCD163, p-mTOR, PROF1, CALM2, CALR, PPIA, or EIF5Al; and(c) comparing the expression level of the biomarker to a control sample.
Instant claim 83 is directed to the method of claim 82, wherein the control sample is a biological sample obtained from: (a) the subject with fibrosis prior to treatment with the caveolin-1 peptide or derivative thereof;(b) a subject or a population of subjects with fibrosis; or (c) a healthy subject.
Instant claim 86 is directed to the method of any one of claim 82,wherein the biological sample is bronchoalveolar lavage fluid (BALF), lung tissue, fibroblasts, type I alveolar epithelial cells, type II alveolar epithelial cells, basal cells, basal-like cells, Clara cells, ciliated cells, club cells, goblet cells, neuroendocrine cells, endothelial cells, bialveolar stem cells, macrophages, alveolar macrophages, ionocytes, pericytes, mesothelial cells, mesenchymal cells, neuroendocrine cells, myofibroblasts, B-cells, plasma cells, innate lymphoid cells, T-cells, monocytes, NK cells, dendritic cells, or PBMCs.
Instant claim 92 is directed to the method of any one of claim 82,wherein the caveolin-1 peptide or derivative thereof is FTTFTVT (SEQ ID NO: 3) or Ac- aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 4).
Instant claim 94 is directed to the method of any one of claim 82,wherein the subject is a human.
Instant claim 95 is directed to the method of any one of claim 82,wherein the fibrosis is interstitial lung disease, liver fibrosis, renal fibrosis, skin fibrosis, glomerulonephritis, systemic sclerosis, cardiac fibrosis, myocardial fibrosis, kidney fibrosis, hepatic cirrhosis, renal sclerosis, arteriosclerosis, macular degeneration, ocular scarring, cataracts, retinal and vitreal retinopathy, Grave's ophthalmopathy, neurofibromatosis, scleroderma, glioblastoma, keloids and hypertrophic scarring, peritoneal fibrotic disease, chronic obstructive pulmonary disease, post- operative fibroids, diabetic nephropathy, gynecological cancer, myeloproliferative syndrome, myeloid leukemia, myelodysplastic syndrome, inflammatory bowel disease, non-alcoholic fatty liver disease, fibrosarcoma, rheumatoid arthritis, non-alcoholic steatohepatitis, Alport syndrome, or chronic COVID syndrome.
Instant claim 96 is directed to the method of claim 95, wherein the interstitial lung disease is idiopathic pulmonary fibrosis, lymphangioleiomyomatosis, nonspecific interstitial pneumonia, idiopathic interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, pulmonary sarcoidosis, diffuse alveolar damage, systemic sclerosis, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, drug-induced interstitial lung disease, or occupational interstitial lung disease.
Instant claim 98 is directed to the method of any one of claim 82,wherein the expression level of the biomarker is measured by 2-D gel electrophoresis, Western blot, mass spectrometry, flow cytometry, quantitative RT-PCR, ELISA, and/or a lateral flow immunoassay; and/or wherein the method further comprises measuring an expression level of an internal control and wherein the expression level of the internal control is unaffected by the caveolin-1 peptide or derivative thereof.
Instant claim 99 is directed to the method of any one of claim 82,wherein the increased expression level of MYDGF, PROF1, CALM2, CALR, PPIA, IF5A1, LGALS7, soluble RAGE or EIF5A1 indicates a favorable response to the caveolin-1 peptide or derivative thereof; or wherein the decreased expression level of PDGFR3, pPDGFR3, p-mTOR, CALR, IL- 11, MMP-2, CXCL7, sCD163, or pSMAD2/3 indicates a favorable response to the caveolin-1 peptide or derivative thereof.
Instant claim 110 is directed to the method of any one of claim 82,wherein steps (a)-(c) of the method are repeated one or more time.
Regarding the limitations of instant claims 1, 82, or 99, Marudamuthu teaches a method for treating a subject with caveolin-1 peptide therapy, wherein the subject is suffering from fibrosis (treating a subject with idiopathic pulmonary fibrosis using CSP 7 (caveolin-1 peptide) therapy; abstract; page 1, 2nd column, 3rd paragraph), the method comprising the steps of: a: obtaining or having obtained a biological sample from the subject; b. treating or having treated a cell of the biological sample with a. caveolin-1 peptide or derivative thereof (lung homogenates or primary fibrotic lung fibroblasts isolated from lung tissue (obtaining or having obtained a biological sample) of subjects were treated with CSP7 (caveolin-1 peptide or derivative thereof); page 2, 1st column, 1st paragraph; page 3, 1st column, 3rd paragraph; page 6, 1st column. 2nd paragraph); c. measuring an expression level of a biomarker in the cell; and d. comparing the expression level of the biomarker to a control sample (Western blotting was performed on lung homogenates and cell lysates for pSMAD2/3 and PDGFR beta, respectively (measuring an expression level of a biomarker in the cell) in fibrotic lung fibroblasts treated either with scrambled control peptide or CSP7 (comparing the expression level of the biomarker to a control sample); page 2, 1st column, 1st paragraph; page 3, 1st column, 3rd paragraph; figs. 1A and S1); and if the expression level of the biomarker is decreased, rather than increased (treatment of fibrotic lung fibroblasts with CSP7 reduced pSMAD2/3 and PDGFR beta expression levels (expression level of the biomarker is decreased); page 2, 1st column, 1st paragraph; page 4, 2nd column, 5th paragraph; figs. 1A and S 1 ), then administering caveolin-1 peptide or derivative thereof to the subject (CSP7 exerts antifibrotic effects by reducing expression levels of pSMAD2/3 and PDGFR beta which are overexpressed in IPF, thereby supporting its use as an antifibrotic treatment, which would intrinsically involve (then) administering CSP7 (i.e. caveolin-1 peptide or derivative thereof) to a patient with IPF (subject); abstract; page 2, 1st column, 1st paragraph; page 3, 1st column. 3rd paragraph; page 4, 2nd column, 5th paragraph: page 5, 1st column, 1st paragraph; fig. 1A).
Regarding the limitations of instant claim 83, Marudamuthu teaches use of control lung tissues from donors without pulmonary fibrosis (see e.g. page 8, right column, last paragraph). These tissues can be from healthy donors (see e.g. Figure 1 legend, page 2).
Regarding the limitations of instant claim 86, the sample taken in Marudamuthu comprises Primary fibrotic lung fibroblasts (fLfs) isolated form human lungs (see e.g. page 2, left column, first paragraph). Marudamuthu also teaches use of bronchoalveolar lavage fluid for samples (see e.g. page 3, left column, third paragraph from top).
Regarding the limitations of instant claim 92, Marudamuthu teaches use the sequence of CSP7 to be FTTFTVT, which is identical to instant SEQ ID NO:3 (see e.g. page 11, left column, third paragraph from top).
Regarding the limitations of instant claims 94-96, Marudamuthu teaches treatment of interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) (see e.g. page 1, left column, first paragraph; page 1, right column, last paragraph; page 3, right column, last paragraph).
Regarding the limitations of instant claim 98, Marudamuthu shows testing of several internal controls when measuring output from various assays. For example, western blots are shown with beta-actin, which is not affected by CSP7 treatment (see e.g. Figure 1C and 1D).
Regarding the limitations of instant claim 110, Marudamuthu states that experiments were repeated two or three times, indicating a repeat of all steps at least one or more times (see e.g. Figure 1 legend, page 2).
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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