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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/14/26 has been entered.
Claim Status
The amendments and arguments filed on 3/18/26 are acknowledged and entered. Claims 2-12 are cancelled. Claims 1 and 13-15 are pending. Claims 1 and 14-15 are amended.
Claims 1 and 13-15 are currently under consideration for patentability under 37 CFR 1.104.
Withdrawn Claim Rejections
The rejection of claims 1 and 13-15 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of Applicant’s amendments thereto. The rejection of claims 6-12 is rendered moot by cancellation of the claims.
The rejection of claims 7-12 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is rendered moot by cancellation of the claim.
Maintained Claim Rejections
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
The rejection of claims 14-15 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 is maintained. The rejection of claims 1 and 13 is withdrawn in light of Applicant’s amendments thereto. The rejection of claim 6-12 is rendered moot by cancellation of the claim. 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 have been amended to recite a compound consisting of one or more peptides consisting of a structure of A-L1-B-L2-C wherein A, B, and C correspond to sequences derived from IL-4 or IL-13. Instant claim 1 has been amended to recite “an amino acid sequence” then naming a sequence and a SEQ ID NO in parentheses. The scope of the term “an amino acid sequence…(SEQ ID NO:)” is indefinite as described in the rejection under 35 USC 112(b) below. The amino acid sequence can also be varied by an amino acid, wherein the substitution can be made to any other amino acid. This level of variability encompasses thousands of possible peptides at best. However, given the “an amino acid sequence” language, even more polypeptides could be encompassed that are only required to have any two amino acids in sequence from the named SEQ ID NO (see also rejection under 35 USC 112(b) below), which produces even more possible peptides. The compound comprising the amino acid sequence must be able to treat all types of neuroinflammatory disorder or treat neuropathies and traumatic nervous system injuries upon administration.
The specification discloses SEQ ID NO:1-6 as possessing the required characteristics. However, the claims are not limited to theses sequences. The claims instead provide for any sequence of any length encompassing any two amino acids in sequence from the SEQ ID NOs named, which can also contain at least one amino acid substitution. There are millions of possible peptides encompassed, given that the peptides can have any sequences of any length added to the ends or as linkers in the protein, all of which must possess the required functions recited in the claims. These peptides have no correlation between their structure and function. The specification provides no guidance regarding which variants 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:1-6, 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.
It is possible, given the language of the claim which includes statements such as "an amino acid sequence WNRSEIIKTGSKTIMREKY (SEQ ID NO:1)", that any two amino acids in sequence would suffice to meet the limitations of the claims. Because function of protein is dependent on the presence of each specific amino acid residue, a wide variety of polypeptides, is encompassed by the instant claim. In addition the phrase “an amino acid sequence” allows any fragment, including any two amino acids in sequence, to be encompassed in the instant claim. This would in theory encompass any possible protein on earth. These peptides have no correlation between their structure and function. The claim requires that the peptide treat three different genera of diseases or conditions, But the specification provides no guidance to which peptides are capable of the required function.
Regarding the encompassed peptides and compounds, 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 variants 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 peptides and compounds 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 SEQ ID NO:1-6, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a). MPEP 2163 states that inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. Given the unpredictable nature of protein function, and absence of evidence of additional species that possess the required functions of the instant claims, Applicant has not provided sufficient evidence to show possession of the broad genus of inadequately described peptide variants , for which neither structure has been provided to correlate to the required functions, nor a representative number of species reduced to practice to demonstrate possession across the breadth of the genus of proteins.
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 SEQ ID NO: 11, and the nucleic acid encoding the protein of SEQ ID NO:9-10, but not the full breadth of the claims, meet the written description provision of 35 USC 112(a).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai 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.
The 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 USPQ2dat1966.
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.
Applicant’s Arguments
Applicant argues:
1. Claim 1 has been amended to remove the functional limitation; therefore the claims meet the requirements under 35 USC 112(a) for written description.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
As advised in the Final Office Action mailed 11/18/25, the amendment to remove the functional language from claim 1 overcomes the rejection for claims 1 and 13. The rejection has been amended above.
However, claims 14 and 15 require specific functions for the peptides, including treating neuroinflammatory disorders, neuropathies, or traumatic nervous system injuries. The instant specification does not set forth adequate structure to correlate with the required function for the encompassed polypeptides, and does not provide a representative number of species for the encompassed polypeptides. Because the polypeptides are not adequately described, the method is inadequately described. Therefore, the rejection is maintained for claims 14 and 15.
Enablement
The rejection of claims 14-15 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement is maintained.
The rejection is updated to reflect the submission of post-filing data that demonstrate that the specification, while being enabling for treating Multiple Sclerosis with a peptide of instant SEQ ID NO:1, does not reasonably provide enablement for treatment of all of the encompassed neuroinflammatory diseases, or treatment of any neurodegenerative diseases, neuropathies, or traumatic nervous system injuries, or prevention of any disorder.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.
nature of the invention; 2) the breadth of the claims;
The instant claims have been amended to recite a compound consisting of one or more peptides consisting of a structure of A-L1-B-L2-C wherein A, B, and C correspond to sequences derived from IL-4 or IL-13. Instant claim 1 has been amended to recite “an amino acid sequence” then naming a sequence and a SEQ ID NO in parentheses. The scope of the term “an amino acid sequence…(SEQ ID NO:)” is indefinite as described in the rejection under 35 USC 112(b) below. The amino acid sequence can also be varied by an amino acid, wherein the substitution can be made to any other amino acid. This level of variability encompasses thousands of possible peptides at best. However, given the “an amino acid sequence” language, even more polypeptides could be encompassed that are only required to have any two amino acids in sequence from the named SEQ ID NO (see also rejection under 35 USC 112(b) below), which produces even more possible peptides. The compound must also be capable of treating all neuroinflammatory disorders, neurodegenerative disorders, neuropathies, and traumatic nervous system injuries.
The polypeptide genus encompassed by the claims is overly broad because the claims provide for any sequence of any length encompassing “an amino acid sequence” of claim 1 (see also rejections under 35 USC 112(a) and 35 USC 112(b)). Even if the peptides are only listed to the SEQ ID NO and the single amino acid variants, thousands of polypeptides are encompassed, all of which must possess the required functions recited in the claims.
Furthermore, the genera of diseases to be prevented or treated are enormously broad. The instant specification does not provide a definitive list of disorders, but instead only describes “preferred” disorders including “all forms of multiple sclerosis (MS), neuromyelitis optica (NMO), Parkinson's disease, Alzheimer's disease or other forms of dementia, amyotrophic lateral sclerosis (ALS) and Huntington's disease” (see e.g. page 16 of the instant specification). Therefore, hundreds, if not thousands, of disorders are 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. Here are some assorted examples:
Neuroinflammation is a state of chronic inflammation within the central nervous system (CNS), which includes the brain and spinal cord. Neuroinflammation can be caused by a variety of factors, including: Infections (e.g., viral, bacterial, fungal); Traumatic brain injury; Stroke; Autoimmune disorders; Oxidative stress; Toxic metabolites, Ageing, Air pollution, and Metabolic disorders (e.g., diabetes). Some selected examples of these disparate disorders include: Acute disseminated encephalomyelitis (ADEM); CNS inflammation due to vaccination reaction; Autoimmune encephalitis; Myelin oligodendrocyte glycoprotein antibody disease (MOGAD); Optic neuritis; Transverse myelitis; Neuromyelitis optica spectrum disorder (NMOSD); Anti-myelin oligodendrocyte glycoprotein antibody disorder (MOG); Multiple sclerosis; Neurosarcoidosis; Rasmussen's syndrome, Acute necrotizing encephalopathy of childhood (ANEC); Cancer; Opsoclonus-myoclonus ataxia syndrome (OMAS); and psychiatric diseases such as Illnesses such as schizophrenia, autism, depression, and other mood disorders that have been linked with inflammation of the brain. Neuroinflammation is a key process in many CNS inflammatory diseases. Alzheimer's disease, Parkinson's disease, and Huntington disease are also linked to neuroinflammation. Neuroinflammation can also occur in many common auto-inflammatory diseases such as eczema, asthma and diabetes. Non-immune diseases with etiological origins in inflammatory processes or which otherwise display inflammatory symptoms include cancer, which includes both primary neurological cancers such as brain tumors (of which there are over 120 different types, some examples of which are meningiomas, pituitary tumors, medulloblastoma, skull base tumors and gliomas), and metastatic cancers that arise from other body tissues but which travel to the brain during cancer progression. This list is not exhaustive and other neurodegenerative diseases exist that also would be encompassed.
Neurodegenerative disorders also have diverse underlying mechanisms and symptoms. Some examples include Alzheimer’s disease, Parkinson’s disease, ALS, Huntington’s disease, Multiple sclerosis, Creutzfeldt-Jakob disease (CJD), Prion diseases, spinocerebellar ataxia, Lewy body dementia, Progressive supranuclear palsy, multiple system atrophy, motor neuron disease, Friedreich’s ataxia, Machado-Joseph disease, Spinocerebellar ataxia, Cerebro-Oculo-Facio-Skeletal (COFS) Syndrome, Corticobasal Degeneration, Gerstmann-Straussler-Scheinker Disease, Infantile Neuroaxonal Dystrophy, Kuru disease, Leigh Syndrome, Mitochondrial DNA Depletion Syndrome (Alpers' Disease), Monomelic Amyotrophy, Myoclonus, Neurodegeneration with Brain Iron Accumulation, Neuronal Ceroid Lipofuscinosis (Batten Disease) Progressive Multifocal Leukoencephalopathy, Alpers-Huttenlocher syndrome, Alpha-methylacyl-CoA racemase deficiency, Andermann syndrome, Ataxia neuropathy spectrum, Autosomal dominant cerebellar ataxia, deafness, and narcolepsy, CLN1 disease, CLN10 disease, CLN2 disease, CLN3 disease, CLN5 disease, CLN6 disease, CLN7 disease, CLN8 disease, Congenital insensitivity to pain with anhidrosis, Familial encephalopathy with neuroserpin inclusion bodies, Fatty acid hydroxylase-associated neurodegeneration, GM2-gangliosidosis, AB variant, Hereditary sensory and autonomic neuropathy type IE, Hereditary sensory and autonomic neuropathy type II, Hereditary sensory and autonomic neuropathy type V, Infantile-onset ascending hereditary spastic paralysis, Juvenile primary lateral sclerosis, Marinesco-Sjögren syndrome, Mitochondrial membrane protein-associated neurodegeneration, Multiple system atrophy, Neuromyelitis optica, Pantothenate kinase-associated neurodegeneration, Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, Progressive external ophthalmoplegia, Riboflavin transporter deficiency neuronopathy, Sandhoff disease, and Spastic paraplegia type 49. This list is not exhaustive and other neurodegenerative diseases exist that also would be encompassed.
There are many types of neuropathies that result from a vast array of causes. For example, there are more than 100 types of peripheral neuropathies including amyloid polyneuropathy, diabetic neuropathy, autonomic neuropathy, inflammatory neuropathy caused by infections or autoimmune processes, toxic neuropathy caused by medications or environmental chemicals, motor neuropathy, sensory neuropathy, and combination neuropathies. Some additional examples of types of neuropathies include Charcot’s Joint (neuropathic arthropathy), cranial neuropathy, compression mononeuropathy, femoral neuropathy, focal neuropathy, thoracic radiculopathy, lumbar radiculopathy, unilateral foot drop. This list is not exhaustive and other types of neuropathy exist that also would be encompassed.
Traumatic nervous system injuries. Traumatic brain injury (TBI) happens when a sudden, external, physical assault damages the brain. It is one of the most common causes of disability and death in adults. TBI is a broad term that describes a vast array of injuries that happen to the brain. The damage can be focal (confined to one area of the brain) or diffuse (happens in more than one area of the brain). The severity of a brain injury can range from a mild concussion to a severe injury that results in coma or even death. Brain injury includes closed brain injuries and penetrating brain injuries. Other injury types include diffuse axonal injury, concussion, blunt traumatic brain injury, cervical spine injuries, thoracic spine injury, lumbar spine injury, and sacral spine injury. This list is not exhaustive and other types of traumatic nervous system injuries exist that also would be encompassed.
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 of the encompassed disorders is underdeveloped. In particular, there is no known agent that is effective to treat or prevent all neuroinflammatory disorders, neurodegenerative disorders, traumatic nervous system injury, and neuropathies.
The inflammatory 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 neuroinflammatory diseases in a subject, with the claimed genus of antibodies 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 inflammatory disease presents challenges beyond initial screening. For example, regarding autoimmune disease such as multiple sclerosis, according to Steinman et al (Nat Med. 2012 Jan 6;18(1):59-65), there are no approved clinical tests that are effective at predicting the therapeutic success or toxicity of treatments for autoimmune diseases (see page 59). Further Steinman et al teach that a single therapeutic strategy is probably not suitable for all immune related diseases or even for individual subsets of patients within one diagnostic category, as there may be heterogeneous biology underlying some of these clinical entities (see page 61). Steinman et al give the example of biologics targeting TNF and its receptors, which are effective in rheumatoid arthritis, Crohn's disease and psoriasis, but which cause marked worsening of disease in multiple sclerosis (see page 60). Blumberg et al (Nat Med.; 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in immune diseases are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3). It is important to remember that the claims are even broader than the field of autoimmune disorders, including diseases such as, for example, infectious diseases, neurodegenerative disease, neuropathies and nervous system injury, which are beyond the scope of autoimmune disorders. Given the extremely broad nature of the encompasses diseases, which have variable etiology and pathology, and the teachings of Steinman and Blumberg, one of skill in the art would not be able to predict the effectiveness of the encompassed antibodies in each of the claimed inflammatory diseases.
The lack of predictability for treatment of neuroinflammatory diseases is confirmed by Cohen (Cells. 2024 Mar 14;13(6):511). Cohen teaches that the exact mechanism of the neuroimmune dysfunctions of the pathogeneses of disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) is currently not clearly understood (see e.g. page 1, abstract). As of 2024, there are still no disease-modifying treatment options currently available for neuroinflammatory disorders and are treated symptomatically (Cohen, page 2, last paragraph). Moreover, drug delivery to the CNS remains a challenge in treating neurodegenerative disorders due to the blood brain barrier (Cohen, page 2, last paragraph). Available drugs address only symptoms (Cohen, page 2, last paragraph).
Further, predicting the success of a treatment for neurodegenerative disease presents challenges beyond initial screening, because success rates for identifying therapeutics that can treat any central nervous system disease fall below the average for other diseases. As taught by Pangalos et al (Nature Reviews Drug Discovery 6, 521-532 (July 2007)), this can be attributed to the need to cross the blood-brain barrier, across which therapeutic agents would need to cross to stimulate autophagy, the sheer complexity of the brain, a propensity for CNS drugs to cause toxic side effects, and a lack of biomarkers available to determine whether the agents are able to reach the brain in sufficient concentrations to modulate the desired target (see page 521, middle column).
Treatment of neuropathies is also unpredictable. Van Velzen et al (Front Pain Res (Lausanne). 2020 Aug 7;1:1) teaches that the origin of neuropathic pain is diverse and related to a large variety of often difficult to treat underlying diseases or lesions (see e.g. page 1). For example, neuropathic pain may occur due to trauma to the central or peripheral nervous system (e.g., surgical trauma, spinal cord injury, complex regional pain syndrome), nerve compression, vascular disease (e.g., stroke), neurological diseases (e.g., multiple sclerosis, syringomyelia), infectious diseases (HIV, leprosy, shingles), metabolic syndromes (diabetic mellitus, sarcoidosis, alcoholism), drugs (e.g., chemotherapeutics) or hereditary syndromes (e.g., Fabry’s disease, erythromelalgia, channelopathy) (see e.g. page 1). In some patients the cause of the neuropathic pain symptoms is unknown (see e.g. page 1). Given the above, the presence of the high variety in underlying processes responsible for neuropathic pain, with additionally all the patient variations expressed within single diseases, precede the notion that treatment will be difficult and should be individualized per patient (see e.g. page 1). There is a complete lack of adequate efficacy of currently available pharmacotherapy (see e.g. page 2, left column). Poor outcomes of randomized trials are translated into clinical practice where doctors and patients are painfully aware of the small effects of currently available treatments (see e.g. page 2, left column).
The art also shows that despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials (see abstract, DeWitt et al, J Neurotrauma. 2018 Dec 1;35(23):2737-2754). TBI in humans is complex and heterogeneous and patients with many different types of TBI (see DeWitt, page 2739, right column). It is likely and reasonable that therapies that show preclinical efficacy in experimental models replicating focal TBI might not necessarily prove equally effective in patients with, for example, diffuse TBI (see DeWitt, page 2739, right column). Unfortunately, it is rarely the case in either clinical or experimental studies that the same targets of therapy are present, and the same mechanisms are active for different TBIs in different patients (see DeWitt, page 2740, left column).
Given the unpredictability in the treatment of neurological disorders as indicated above, the skilled artisan would not be able to reasonably predict the outcome of the claimed method, i.e. would not be able to accurately predict if an agent would be able to perform the functions in the claimed method without undue experimentation.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
Applicant has described six specific peptides encompassed by the claims, which are represented by SEQ ID NO:1-6. The specification describes in vitro studies performed in cell cultures with different peptides than recited in the instant claims, in particular “Link” peptides called Link4 and AvoC, which are IL-4 derivative peptides, and Link 13, which is an IL-13 derivative peptide. Further, the specification describes experiments in EAE mouse models (i.e. experimental autoimmune encephalomyelitis), which has been most commonly used as a model for multiple sclerosis (see e.g. page 1 of Robinson et al (Handbook of Clinical Neurology, Volume 122, 2014, Pages 173-189)), but is also recognized as differing in many aspects from human disease (see e.g. Robinson, page 4). The experiments with the EAE mouse model were limited to testing of nasally applied IL-4 and Link4 peptide. However, none of the claimed peptides were tested in any in vitro or mouse model. The peptides that were tested are not described as fusion proteins of the instant claims. Therefore, the specification relies on prophetic examples for a wide range of claimed peptides to enable treating vast genera of highly unpredictable diseases that are arise from different pathological mechanisms. One of skill in the art would first be required to identify an encompassed protein with the required features of stimulating neuronal axon outgrowth and having no side effects on lymphocytes or bone marrow derived macrophages (the latter of which is notably not defined by the specification), then perform experiments to match the selected peptides with diseases that can be prevented or treated with the claimed peptides. To say that the required experimentation is undue would be an understatement. Additionally, there is no agent known to prevent neurological diseases, no known model system exists to test this function, and applicant has not offered any evidence that any claimed peptide could perform this function.
In conclusion, the claimed invention does not provide enablement for the claimed compound which must have specific ability to treat all neuroinflammatory disorders, neurodegenerative disorders, traumatic nervous system injury, and neuropathies. 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.
Applicant’s Arguments
Applicant argues:
The claims have been amended to restrict the breadth of the claimed compounds.
The specification is not required to describe how to make and use each and every possible variant of the claimed invention.
Applicant argues that the Examiner has failed to take into account the amount of direction or guidance provided by the specification, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Applicant argues that the application describes sufficiently the subject matter so that one of skill in the art would reasonably conclude that the claims are enabled for the full breadth of protection desired or do not require undue experimentation to make and use the claimed invention. Applicant argues that the Examiner has failed to take into account the amount of direction or guidance provided by the specification, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure. Applicant’s invention is directed toward novel peptide compounds that are derived from human or animal interleukin-4 or interleukin-13 in a treatment or prevention of neuroinflammatory disorders or neurodegenerative disorders. The nature of the claims are limited because the specification teaches that the biological activity is defined by capability to bind to IL-4R type I or II, wherein the binding of the peptide or variant of the invention results in the desired neuroprotective and neurodegenerative effects. Applicant indicates that the biological effects can be measured by in vitro or in vivo systems such as EAE or mouse models for MS.
The Examiner’s analysis fails to take into account the amount of direction or guidance provided in the specification, existence of working examples, and quantity of experimentation needed to make or use the invention. Even if the art is unpredictable, Applicant has provided sufficient disclosure to overcome those factors. Applicant also notes that the skill in the art is high. The specification further details various testing methods. Applicant was able to show that IL-4 and IL-13 derivatives in accordance with the instant invention act on neurons in the same way as IL-4 but without the side effects of affecting lymphocyte populations or myeloid cells. Applicant also points to “in vivo” effects on axon morphology, and neurite outgrowth. The biological activity of the derivative peptides “was believed to be due to the structural features and common binding principles”. Applicant further showed that IL-4 derivatives were not toxic and exhibited beneficial effects on EAE mouse models. Applicant has further provided a declaration by Dr. Vogelaar to show that the peptides of the amended claims are “likely to have the claimed effects”. Applicant further claims that IL-4 is known to have beneficial effects in experimental models of CNS disease.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. The instant claims have been amended to recite a compound consisting of one or more peptides consisting of a structure of A-L1-B-L2-C wherein A, B, and C correspond to sequences derived from IL-4 or IL-13. Instant claim 1 has been amended to recite “an amino acid sequence” then naming a sequence and a SEQ ID NO in parentheses. The scope of the term “an amino acid sequence…(SEQ ID NO:)” is indefinite as described in the rejection under 35 USC 112(b) below. The amino acid sequence can also be varied by an amino acid, wherein the substitution can be made to any other amino acid. This level of variability encompasses thousands of possible peptides at best. However, given the “an amino acid sequence” language, even more polypeptides could be encompassed that are only required to have any two amino acids in sequence from the named SEQ ID NO (see also rejection under 35 USC 112(b) below), which produces even more possible peptides. Therefore the scope of the encompassed polypeptides is still overbroad and the rejection is therefore maintained.
2. The Examiner has not required that Applicant describe each and every encompassed species of the invention, and therefore Applicant’s argument is moot.
3. The Examiner has not failed to take into account the amount of direction or guidance provided by the specification, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The rejection specifically sets forth the following section, which specifically discusses the experimentation in the specification, and describes how this experimentation does not meet the requirements for enabling the full scope of the invention:
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
Applicant has described six specific peptides encompassed by the claims, which are represented by SEQ ID NO:1-6. The specification describes in vitro studies performed in cell cultures with different peptides than recited in the instant claims, in particular “Link” peptides called Link4 and AvoC, which are IL-4 derivative peptides, and Link 13, which is an IL-13 derivative peptide. Further, the specification describes experiments in EAE mouse models (i.e. experimental autoimmune encephalomyelitis), which has been most commonly used as a model for multiple sclerosis (see e.g. page 1 of Robinson et al (Handbook of Clinical Neurology, Volume 122, 2014, Pages 173-189)), but is also recognized as differing in many aspects from human disease (see e.g. Robinson, page 4). The experiments with the EAE mouse model were limited to testing of nasally applied IL-4 and Link4 peptide. However, none of the claimed peptides were tested in any in vitro or mouse model. The peptides that were tested are not described as fusion proteins of the instant claims. Therefore, the specification relies on prophetic examples for a wide range of claimed peptides to enable treating vast genera of highly unpredictable diseases that are arise from different pathological mechanisms. One of skill in the art would first be required to identify an encompassed protein with the required features of stimulating neuronal axon outgrowth and having no side effects on lymphocytes or bone marrow derived macrophages (the latter of which is notably not defined by the specification), then perform experiments to match the selected peptides with diseases that can be prevented or treated with the claimed peptides. To say that the required experimentation is undue would be an understatement. Additionally, there is no agent known to prevent neurological diseases, no known model system exists to test this function, and applicant has not offered any evidence that any claimed peptide could perform this function.
4. The arguments are not persuasive. First, the rejection is one of enablement, which is the ability to make and use an invention, and therefore Applicant is applying the wrong standard when referring to whether the application is sufficiently described.
Second, Applicant has mischaracterized the rejected claims. Applicant has stated that “Applicant’s invention is directed towards novel peptide compounds”. This is simply not true. The rejected claims are directed to a method of treatment that uses the novel peptide compounds.
Third, the Examiner disagrees that the nature of the claims are limited. The claims are in fact extremely broad, and are directed to treating or preventing any disease or disorder that would fall within the categories of neuroinflammatory or neurodegenerative disorders, or that involve neuropathies or traumatic nervous system injuries. The breadth of the claims is further exacerbated by the thousands of possible peptides that could be administered, each with a unique amino acid sequence. There are millions of possible combinations of diseases with the claimed peptides. Further, Applicant attempts to group the disorders as being similar based on the location of the diseases in the neurological systems of the body, but in fact the molecular mechanisms underlying each of these diseases is distinct, and each disease or disorder has a different set of pathological features and symptoms that develop during the course of the disease. Further, Applicant has not demonstrated any connection between any of the in vitro studies and the mechanisms that cause the diseases and disorders that are encompassed by the claims that would suggest that the claimed peptides offer any treatment or prevention of any disease, and no such connection is apparent in the art. Further, as provided in the references above, treatment of various encompassed neurological disorders is unpredictable at best. Without guidance by the inventor, one of skill in the art would be required to perform undue experimentation to establish a nexus between the mechanism of the claimed polypeptides and the vast range of diseases that are encompassed by the instant claims. The mere “belief” that a particular activity corresponds to in vivo activity, or that it is “believed to be due to the structural features and common binding principles,” as it is described in Applicant’s own arguments, is not evidence that the claimed peptides are capable of treating a broad genus of otherwise unrelated disorders.
As stated above, the experiments in the instant specification with the EAE mouse model were limited to testing of nasally applied IL-4 and Link4 peptide. Notably none of the claimed peptides were tested in any in vitro studies or mouse model in the instant specification. The peptides that were tested in the specification are not described as fusion proteins of the instant claims. In fact, with the exception of the post-filing data regarding instant SEQ ID NO:1, Applicant is relying on demonstrating enablement by referring to activities of entirely different proteins that are not recited in the instant claims. The specification only presents entirely prophetic examples for using the claimed peptides, which are based on potential segments for a hypothetical fusion proteins, to enable treating vast genera of highly unpredictable diseases that arise from different pathological mechanisms, without even testing the claimed peptides. One of skill in the art would first be required to identify an encompassed protein with the required features of stimulating neuronal axon outgrowth and having no side effects on lymphocytes or bone marrow derived macrophages (the latter of which is notably not defined by the specification), then perform experiments to match the selected peptides with diseases that can be prevented or treated with the claimed peptides. To say that the required experimentation is undue would be an understatement. Additionally, Applicant has failed to consider that there is no agent known to prevent neurological diseases, no known model system to test this function, and applicant has not offered any evidence that any claimed peptide could perform this function.
5. The argument is not persuasive. The amount of direction presented in the instant specification and the working examples presented provide are very narrow in their application compared to the wide breadth of the claims at issue here. The claims are directed to treating or preventing any disease or disorder that would fall within the categories of neuroinflammatory or neurodegenerative disorders, or that involve neuropathies or traumatic nervous system injuries. The molecular mechanisms underlying each of these diseases is distinct, and each disease has a different set of pathological features and symptoms that develop.
As stated above, none of the claimed peptides were tested in any in vitro or mouse model. The peptides that were tested are not described as fusion proteins of the instant claims. Therefore, the specification relies on prophetic examples for a wide range of claimed peptides to enable treating vast genera of highly unpredictable diseases that are arise from different pathological mechanisms. One of skill in the art would first be required to identify an encompassed protein with the required features of stimulating neuronal axon outgrowth and having no side effects on lymphocytes or bone marrow derived macrophages (the latter of which is notably not defined by the specification), then perform experiments to match the selected peptides with diseases that can be prevented or treated with the claimed peptides. To say that the required experimentation is undue would be an understatement.
At best, the studies described in the specification investigate the activity of proteins that are not claimed. Even these limited peptides, which are not encompassed by the instant claims, have only been tested in a single model, which is the EAE mouse model. The instant specification states that this model is a mouse model for multiple sclerosis (see page 2 of the instant specification). This mouse model is not stated to have any relevance to nervous system injuries, neuropathies, or neurodegenerative disorders, or to any other neuroinflammatory disorders.
The Declaration by Dr. Vogelaar also does not provide sufficient enablement for the claimed invention, except for the treatment of Multiple Sclerosis with a peptide having the amino acid sequence of instant SEQ ID NO:1. The rejection has been updated to reflect the newly provided in vivo data. The Declaration otherwise provided data related to in vitro kinase activity and kinase activity arrays on murine dissociated neurons using the hLink-4 peptide. The Declaration further offered in silico data, which is computer generated prediction of activity that does not actually require physical testing of the peptide. The Declaration showed that hLink-4 was able to enhance TrkB activation, which was abolished in the presence of Dupilumab, an IL-4R blocking antibody. Notably, the studies included only a single tested peptide that is encompassed by the instant claims.
The one example of hLink-4, in a series of in vitro studies and a single mouse model that does not have relevance to any other recited disorder, is simply not sufficient to support enablement of treatment and prevention of hundreds of disorders with different pathologies and etiologies, each of which may or may not involve any signaling related to the claimed peptides. Applicant has provided no evidence that any other claimed peptides have similar activity in vivo. Further, neither the specification nor the Declaration provide a sufficient nexus between the activity of the other tested peptides, which are not encompassed by the specification, and treatment or prevention of disease with the claimed peptides. Dr. Vogelaar’s opinion is not sufficient to establish such a link without factual evidence. See MPEP 2164.05. The weight to give a declaration or affidavit will depend upon the amount of factual evidence the declaration or affidavit contains to support the conclusion of enablement. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991) (Stating that an "expert’s opinion on [an] ultimate legal conclusion must be supported by something more than a conclusory statement").
For these reasons, the Declaration under 37 CFR 1.132 filed 8/14/25 is insufficient to overcome the rejection of claims 14-15 as set forth in the last Office action. Ultimately, the amount of direction presented and the number of working examples provided in the specification are very narrow compared to the wide breadth of the claims at issue, the treatment and prevention of a vast number of diseases that have disparate underlying mechanisms is highly unpredictable, and the amount of experimentation necessary to adapt the findings for a single peptide in a single mouse model to hundreds of disorders and thousands of peptides species is undue.
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 and 13-15 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 several sequences with language such as “consisting of an amino acid sequence WNRSEIIKTIMREKY (SEQ ID NO:1). It is unclear from the language if the term “an amino acid sequence” is referencing the specific sequence enumerated in the claim, or if the term references any two amino acids in sequence selected from the enumerated amino acid sequence. Amending the claim to recite “consisting of the amino acid sequence WNRSEIIKTGSKTIMREKY (SEQ ID NO:1)” or “consisting of the amino acid sequence set forth as SEQ ID NO:1 for every instance where the language appears would overcome the rejection.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/ Examiner, Art Unit 1674
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