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 .
It appears the inventor(s) filed the current application pro se (i.e., without the benefit of representation by a registered patent practitioner). While inventors named as applicants in a patent application may prosecute the application pro se, lack of familiarity with patent examination practice and procedure may result in missed opportunities in obtaining optimal protection for the invention disclosed. The inventor(s) may wish to secure the services of a registered patent practitioner to prosecute the application, because the value of a patent is largely dependent upon skilled preparation and prosecution. The Office cannot aid in selecting a patent practitioner.
A listing of registered patent practitioners is available at https://oedci.uspto.gov/OEDCI/. Applicants may also obtain a list of registered patent practitioners located in their area by writing to Mail Stop OED, Director of the U.S. Patent and Trademark Office, P.O. Box 1450, Alexandria, VA 22313-1450.
Specification
The amendment to the specification filed on 7/9/25 has been entered.
Claim Rejections - 35 USC § 112
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 6-8 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.
In the claims filed on 2/17/25, claims 6-8 recites the limitation "the second tag" in claim 5. There is insufficient antecedent basis for this limitation in the claim because claim 5 does not recite a second tag. The tag in part (ii) of claim 5 is recited in the alternative to the “first tag” in part (i) of the claim and would therefore still be the first tag if the tag in part (i) was not present. Parts (i) and (ii) are not required together resulting in two tags, but rather are recited in the alternative.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-17 and 19-24 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.
Claims 20 and 24 require for the subject to require to treat “any muscle wasting condition and/or fat accumulation due to obesity, lack of physical activity, poor nutrition, neurological problems, medical conditions, and genetic disorders”, which is a genus that has not been adequately described in the specification. The specification discloses sarcopenia and cancer cachexia, which are minimal species that are not representative of the entire claimed genus. The specification does not describe any other muscle wasting condition and/or fat accumulation due to obesity, lack of physical activity, poor nutrition, neurological problems, medical conditions, and genetic disorders to adequately describe the entire claimed genus.
The specification discloses that the genus includes muscle-wasting-related diseases. Without further description of the genus, one would not be able to readily recognize which conditions are related in any manner to muscle wasting. Therefore, one would not be able to recognize that applicant was in possession of the entire genus at the time of filing.
Additionally, the claims recite delivery of peptide sequences differing from FST288 by an insertion, deletion, and/or substitution of one or any number of peptides while still retaining the ability to achieve the recited outcomes. The specification does not adequately describe the structure required for the function. The specification does not describe what level of insertion, deletion, and/or substitution of any number of peptides would result in the ability for the agent to retain the recited activities. The specification does not disclose even a single species of variants that would have the recited functions.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species within the instantly recited genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues: “The specification focused to describe about the drug with respect to its nature and structure, method of manufacturing, application method, dosing amount/frequency. The therapeutic application of the drug (FST288) has been described in the relevant sections in the specification while discussing the function of FST288 in preclinical experiment. The applicant reasonably feels that the specification has been drafted concisely with all relevant information.
The specification describes about the in vivo function and possible application of FST288 as a drug for the treatment of disease conditions. The Background of The Innovation section of the application described the disease conditions and associated state of impaired health or abnormal functioning of the body. Muscle atrophy has been described in greater detail and the consequences associated with the muscle wasting has been discussed (line numbers 50, 62-68, 74-76, 81-84, 206- 207 of this paper).
Sarcopenia has been discussed in the specification to describe the concern and burden associated with the disease (line numbers 44, 90-119, 192 of this paper).
The health concern associated with obesity has been discussed in the specification (line numbers 45, 46, 120-164, 198, 298 of this paper).
The health problem associated with cachexia in cancer patients has been discussed in the specification (line numbers 44, 69-73, 192, 194, 296 of this paper).
The importance of physical activity has been discussed in the specification (line numbers 61, 62, 107,139, 270, 293 of this paper).
The problem of poor nutrition in maintaining good health has been discussed in the specification (line numbers 64-65, 98, 299 of this paper).
Illness caused by neurological problems has been discussed in the specification (line numbers 74- 79, 97, 299 of this paper).
Medical conditions that cause muscle atrophy and obesity has been discussed in the specification (line numbers 65-68, 80-83, 299 of this paper).
Effect of genetic disorder in the muscle wasting and obesity has been discussed in the specification (line numbers 86-89, 153-154, 299 of this paper).”
Applicant appears to be pointing to literal support for the claim language rather than to description of the recited genuses. It is agreed that the specification discloses the recited genus, but the specification does not adequately describe the genuses for one to reasonably recognize that applicant was in possession of the entire genus at the time of filing.
For example, although the specification discloses that the present invention “may be useful as a treatment for muscle-wasting conditions like sarcopenia and cancer cachexia” (page 1), the specification does not adequately describe the genus via giving any criteria for which conditions necessarily are considered muscle-wasting other than sarcopenia and cachexia. Without further description in the specification, one would not be able to readily recognize which other conditions are necessarily included or excluded from the genus.
Claims 20 and 24 require for the subject to require to treat “any muscle wasting condition and/or fat accumulation due to obesity, lack of physical activity, poor nutrition, neurological problems, medical conditions, and genetic disorders”, which is a genus that has not been adequately described in the specification. The specification discloses sarcopenia and cancer cachexia, which are minimal species that are not representative of the entire claimed genus. The specification does not describe any other muscle wasting condition and/or fat accumulation due to obesity, lack of physical activity, poor nutrition, neurological problems, medical conditions, and genetic disorders to adequately describe the entire claimed genus.
The specification discloses that the genus includes muscle-wasting-related diseases. Without further description of the genus, one would not be able to readily recognize which conditions are related in any manner to muscle wasting. Therefore, one would not be able to recognize that applicant was in possession of the entire genus at the time of filing.
The specification does not set forth any specific criteria to describe the genus so that one would be able to readily recognize which conditions are included or excluded from the genus.
A mere statement in the specification that the method is useful in treating the
conditions due to muscle wasting and increased fat accumulation is not sufficient to adequately describe which conditions are included or excluded from this broadly recited genus.
Applicant argues: “The entire application one peptide FST288 has been considered, and it is considered to have the efficacies in reducing/reversing muscle atrophy at the same time reducing fat accumulation. There is no other sequence mentioned in the application. For the main purpose of purification Tags have been included in either N-terminus or C-terminus of the peptide or at both the terminuses. However, the tags will not be internal to the 288 amino acids core of the FST288.
Addition of tags are variations as additional sequences are attached. Addition of tags has been described in the specifications (line number 226-228 of this paper) and standard tags such as His- tags (i.e., polyhistidine-tags), GST tags (i.e., glutathione S- transferase tags), and FLAG-tags (i.e., DYKDDDDK tags) has been described.”
However, the claims recite that the peptide sequence can differ from FST288 by insertion, deletion, and/or substitution of one or more peptides while still retaining some efficacy in treating sarcopenia or cancer cachexia. The specification discloses a single FST288 sequence and that a tag can be attached. This is not the same as any quantity and location of insertion, deletion, and/or substitution of one or more peptides. The specification does not adequately describe the structure required for the recited function of retaining some efficacy in treating sarcopenia or cancer cachexia.
The specification does not describe what level of insertion, deletion, and/or substitution of any number of peptides would result in the ability for the agent to retain the recited activities. The specification does not disclose even a single species of variants that would have the recited functions.
Claims 5-17 and 19-24 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 delivery of FST288 at a concentration of 500 ng/mL or 1000 ng/mL with a resultant increase in tritiated thymidine corporation, does not reasonably provide enablement for a method of treating any sarcopenia, any cancer cachexia, absolute prevention/reversing any muscle loss, reducing any fat accumulation, increasing any endurance or sprinting activity, treating any muscle-wasting condition, treating any excess fat accumulation associated with various conditions or factors, improving any ambulatory activity, changing any body composition with an increased lean mass/fat mass ratio, treating any possible type of cancer, and treating Alzheimer’s disease via delivery via any route and any amount of at least one of (i) FST288 with a first tag attached and any possible peptide sequence that meets the limitation of: (ii) one or more peptide sequences with a tag attached, the one or more peptide sequences differing from FST288 by an insertion, deletion and/or substitution of one or more peptides while still retaining some efficacy in treating the full breadth of each of the instantly recited conditions. 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/or use the invention commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of treating any sarcopenia, any cancer cachexia, absolute prevention/reversing any muscle loss, reducing any fat accumulation, increasing any endurance or sprinting activity, treating any muscle-wasting condition, treating any excess fat accumulation associated with various conditions or factors, improving any ambulatory activity, changing any body composition with an increased lean mass/fat mass ratio, treating any possible type of cancer, and treating Alzheimer’s disease via delivery via any route and any amount of at least one of (i) FST288 with a first tag attached or any possible peptide sequence that meets the limitation of: (ii) one or more peptide sequences with a tag attached, the one or more peptide sequences differing from FST288 by an insertion, deletion and/or substitution of one or more peptides while still retaining some efficacy in treating the full breadth of each of the instantly recited conditions.
The specification demonstrates delivery in vitro of FST288 at a concentration of 500 ng/mL or 1000 ng/mL with a resultant increase in tritiated thymidine corporation. The specification demonstrates in Figure 1 that 10, 50, and 200 ng/mL was ineffective. Additionally, demonstration of increase in tritiated thymidine corporation is not representative of treatment of any muscle wasting condition or any of the other recited conditions. The specification discloses “This data suggests that FST288 at a concentration of 500 ng/ml and above may be a growth stimulator whereas, below 500 ng/ml, FST288 may not have a comparable proliferative effect. (page 15).
Additionally, the example is not directed to delivery of FST288 with a tag and/or a variant with a tag.
The claims are directed to delivery of FST288 with a tag and a variant of FST288 with a tag. The specification does not disclose any evidence or examples of delivery of FST288 with a tag and the predictable treatment of even a single species of the recited enormous genus of conditions. The claims additionally recite delivery of peptide sequences differing from FST288 by an insertion, deletion, and/or substitution of one or any number of peptides while still retaining the ability to achieve the recited outcomes. The specification does not demonstrate even a single species of variants with a tag that results predictably in each of the instantly recited outcomes.
The specification does not draw an adequate nexus between delivery of FST288 and any tag and/or any one or more peptide sequences with any second tag attached, wherein the one or more peptide sequences differ from FST288 by an insertion, deletion, and/or substitution of one or any number of peptides while still retaining the ability to achieve the recited outcomes.
The specification does not define prevention and the specification is not enabling for absolute prevention of any of the recited conditions via the instant method steps. The specification is not enabling for treatment of any and all cancers, or each of the recited possible conditions, via the instant method steps alone. With regards to cancer, applicant has not demonstrated that delivery of any FST or any FST variant with any tag would result in treatment of any cancer.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of the instantly recited agents in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment or prevention of each of the recited genuses of conditions. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues: Expression and purification of the peptide is important to be useful as a therapeutic molecule. As a result, expression and purification of FST288 has been described in detail in the specification (line number 235-256 of this paper). The purification also includes the procedure to remove bacterial endotoxins if that copurifies with the peptide.
This argument is not believed to be pertinent to the instant rejection because the claims do not require a purification method.
Applicant has set forth that the enabled embodiment set forth by the examiner (delivery of FST288 at a concentration of 500 ng/mL or 1000 g/mL with a resultant increase in tritiated thymidine corporation), is an assay system of testing toxicity of FST288. This is an in vitro assay performed on cultured cell line MPC11. This is a method of quality control to ensure possible contamination of bacterial endotoxin in the preparation. This method is not related to the application of FST288 to a person and this method does not claim for any cure of any disease or conditions mentioned in the application.
It is understood that the enabled embodiment is not directed to treatment. The examiner was pointing out what is actually exemplified in the specification, which is not a treatment method. It is understood that the enabled embodiment is not the claimed method. The examiner set forth the enabled embodiment to differentiate between the enabled embodiment of the specification and the instant claim scope.
Applicant argues that the inclusion of His-tag has been mentioned in the specification (line numbers 227, 236, 240 of the paper). For the purpose of improving the purification efficiency tags are used.
It is noted that mention in the specification is not sufficient for enablement of the entire claimed scope. The specification does not draw an adequate nexus between broad systemic administration of any FST288 with any tag attached (or the variants of claim 5, part (ii)) and the predictable treatment of any sarcopenia or cancer cachexia.
Applicant argues: There is evidence that FST288 will be a therapeutic agent in curing multiple disease conditions. The drug development proceeds from the preclinical studies to the clinical research. Therapeutic application of FST288 in clinical trial will be the future direction of the project and the clinical study is yet to be established. However, preclinical study of FST288 has been established (it is not in a hypothetical phase).
Hypothesis of FST288 being therapeutic is not enabling for a method of broad systemic administration of any FST288 with any tag attached (or the variants of claim 5, part (ii)) and the predictable treatment of any sarcopenia or cancer cachexia. Applicant cannot get a patent to a hypothetical method. The method must be enabled over its entire claim breadth. It appears that applicant has acknowledged that the claim breadth is not currently enabled.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Applicant argues: As referenced in the specification (line number 277-279 of this paper) efficacy of FST288 in promoting muscle growth, concomitantly reducing fat accumulation has been described ["Systemic administration of Follistatin288 increases muscle mass and reduces fat accumulation in mice," Sci Rep. 3:2441 (2013) doi:10.1038/srep02441].
The specification references the paper (Sci Rep. 3:2441 (2013)), which does not demonstrate treatment of sarcopenia or cancer cachexia via systemic administration of any FST288 with any tag attached (or the variants of claim 5, part (ii)). The paper discloses His-tagged (not commensurate in scope with any tag) FST288 (a specific sequence, not any FST288 differing from insertion, deletion, and/or substitution of one or more peptides) in a purification method (page 2). As set forth by applicant, the method is a quality control for toxicity, not a therapeutic method.
Applicant argues that applicant (as well as the author of the paper, Samudra S. Gangopadhyay) established the efficacy of FST288 by in vivo experiments. The applicant is the first to show the function of FST288 peptide in promoting muscle growth, reducing fat accumulation and promoting physical activity. The patent of Kumar et al. and the publication of Yaden et al. came out after the discovery of the applicant. Although the examiner is giving credit to Kumar et al. and Yaden et al., the applicant requests the recognition of the invention of the applicant.
The references cited by the examiner each teach different aspects of the instant claims, each applicable as prior art due to the publication dates. With respect to the instant rejection under 35 USC 112, the references are not enabling for the instant claim scope.
Additionally, although applicant asserts that FST288 is recited in claim 5, part (ii) allows variation from any specific FST288 sequence.
The specification does not demonstrate delivery of FST288 and a tag with the predictable treatment of sarcopenia or cancer cachexia, but rather hypothesizes such.
Applicant argues that testing therapeutic applicability of FST288 in clinical study will be the next step of the ongoing research. This statement supports lack of enablement of the instant claim breadth.
It is noted that instant claim 5 is not directed to any specific composition that has been demonstrated by applicant to have an unexpected result. The claim is directed to delivering, by any mode of administration, FST288 attached in any manner to any tag or delivery, by any mode of administration, one or more peptides differing from FST288 by insertion, deletion, or substation of any number of peptides while still retaining some efficacy. Although applicant argues that the claims are based on only one biologic peptide FST288, the claim breadth is much broader and the specification is not even enabling for FST288 without variation for each of the instantly recited outcomes.
Claim Rejections - 35 USC § 103
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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 5-17 and 19-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kumar et al. (US 11,001,614 B2), in view of Krasney et al. (WO 2008/030367 A2), and Yaden et al. (J Pharmacol Exp Ther, 349, 355-371, 2014).
It is noted that claims 19-23 recite outcomes rather than required method steps and therefore would necessarily flow from the recited method steps of the base claims. Additionally, the references are considered as enabled as the instant specification.
Kumar et al. teach that inhibition of myostatin activity may be an effective strategy for increasing muscle mass and strength in patients with inherited and acquired clinical conditions associated with debilitating muscle loss. Studies with mouse models of muscle disease have suggested that loss of myostatin signaling has beneficial effects in a wide range of disease settings, including muscular dystrophy, spinal muscular atrophy, cachexia, steroid-induced myopathy, and age-related sarcopenia. Moreover, loss of myostatin signaling has been shown to decrease fat accumulation and improve glucose metabolism in models of metabolic diseases, raising the possibility that targeting myostatin may also have applications for diseases such as obesity and type 2 diabetes. Thus there is considerable interest in identifying methods for therapeutic inhibition of myostatin signaling in vivo (column 7).
Kumar et al. teach that best studied among extracellular inhibitors of myostatin, activins, and/or GDF11 is follistatin, a single gene (FST) from which are generated multiple isoforms. Follistatin is an autocrine glycoprotein expressed in nearly all tissues of higher animals. It was initially isolated from follicular fluid and was identified as a protein fraction that inhibited follicle-stimulating hormone (FSH) secretion from the anterior pituitary. The importance of follistatin in TGFβ superfamily signaling is illustrated by the multiple defects and perinatal death observed in follistatin-deficient mice. Postnatally, follistatin promotes muscle growth by inhibiting myostatin and activins and potentially GDF11. The biologic activity of follistatin stems from its ability to bind these ligands with high affinity and thereby prevent interaction of the ligand with its cell-surface receptor—ActRIIA or ActRIM. In addition, follistatin contains a heparin-binding domain that in some isoforms facilitates follistatin interaction with proteoglycans at the cell surface, thereby maintaining higher concentrations of follistatin near the sites of ligand action. Furthermore, binding of follistatin (FST288) to myostatin substantially increases the affinity of follistatin for heparin, thereby suggesting that ligand binding promotes cell-surface localization of the follistatin-myostatin complex (column 10).
Kumar et al. teach that the human follistatin-288 (FST288) precursor has the following amino acid sequence (SEQ ID NO: 1) (NCBI Reference Sequence NP_006341; Uniprot P19883-2), with the signal peptide indicated by dotted underline, the N-terminal domain (FST.sub.ND) indicated by dashed underline, and the follistatin domains 1-3 (FST.sub.FD1, FST.sub.FD2, FST.sub.FD3) indicated by solid underline.
(21) TABLE-US-00001 (SEQ ID NO: 1) 1 51 101 GPGKKCRMNK KNKPRCVCAP DCSNITWKGP VCGLDGKTYR NECALLKARC 151 KEQPELEVQY QGRCKKTCRD VFCPGSSTCV VDQTNNAYCV TCNRICPEPA 201 SSEQYLCGND GVTYSSACHL RKATCLLGRS IGLAYEGKCI KAKSCEDIQC 251 TGGKKCLWDF KVGRGRCSLC DELCPDSKSD EPVCASDNAT YASECAMKEA 301 ACSSGVLLEV KHSGSCN
(22) The mature (processed) human follistatin variant FST288 has the following amino acid sequence (SEQ ID NO: 2) with the N-terminal domain indicated by dashed underline and the follistatin domains 1-3 indicated by solid underline. Moreover, it will be appreciated that any of the initial amino acids G or N, prior to the first cysteine may be removed by processing or intentionally eliminated without any consequence, and polypeptides comprising such slightly smaller polypeptides are further included.
(23) TABLE-US-00002 (SEQ ID NO: 2) 1 51 101 PVCGLDGKTY RNECALLKAR CKEQPELEVQ YQGRCKKTCR DVFCPGSSTC 151 VVDQTNNAYC VTCNRICPEP ASSEQYLCGN DGVTYSSACH LRKATCLLGR 201 SIGLAYEGKC IKAKSCEDIQ CTGGKKCLWD FKVGRGRCSL CDELCPDSKS 251 DEPVCASDNA TYASECAMKE AACSSGVLLE VKHSGSCN (columns 12 and 13).
Kumar et al. teach that any of the follistatin-related polypeptides disclosed herein may be combined with one or more additional follistatin-related polypeptides of the disclosure to achieve a desired effect such as treating a follistatin-related disorder (e.g., increase muscle mass and/or strength in a subject in need thereof, treat or prevent muscle loss in a subject in need thereof, treat or prevent one or more complications of muscle loss in a subject in need thereof; increase hemoglobin concentration or red blood cell count in a subject in need thereof, treat or prevent inadequate hemoglobin concentration or red blood cell count in a subject in need thereof, treat or prevent one or more complications of inadequate hemoglobin concentration or red blood cell count in a subject in need thereof; increase bone mass and/or strength in a subject in need thereof, treat or prevent bone loss or fragility in a subject in need thereof, treat or prevent one or more complications of bone loss or fragility in a subject in need thereof; or treat cancer in a subject in need thereof). For example, a follistatin polypeptide disclosed herein can be used in combination with i) one or more additional FLRG polypeptides disclosed herein, ii) one or more WFIKKN1 polypeptides disclosed herein, and/or iii) one or more WFIKKN2 polypeptides disclosed herein (column 50).
Kumar et al. teach that compositions of the present disclosure, including for example various protein complexes comprising follistatin-related fusion polypeptides disclosed herein, can be used for treating or preventing a disease or condition that is described in this section, including diseases or disorders that are associated with abnormal activity of a follistatin-related polypeptide and/or a follistatin ligand (e.g., myostatin, activins, GDF11). These diseases, disorders or conditions are generally referred to herein as “follistatin-associated conditions.” In certain embodiments, the present disclosure provides methods of treating or preventing an individual in need thereof through administering to the individual a therapeutically effective amount of a follistatin-related fusion polypeptide as described above. These methods are particularly aimed at therapeutic and prophylactic treatments of animals, and more particularly, humans.
(177) As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. The term “treating” as used herein includes amelioration or elimination of the condition once it has been established. In either case, prevention or treatment may be discerned in the diagnosis provided by a physician or other health care provider and the intended result of administration of the therapeutic agent.
(178) In general, treatment or prevention of a disease or condition as described in the present disclosure is achieved by administering a follistatin-related polypeptide, or compositions, complexes or combinations comprising such polypeptide, of the present disclosure in an “effective amount”. An effective amount of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A “therapeutically effective amount” of an agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agent to elicit a desired response in the individual. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.
(179) Follistatin-ligand complexes play essential roles in tissue growth as well as early developmental processes such as the correct formation of various structures or in one or more post-developmental capacities including sexual development, pituitary hormone production, and creation of muscle. Thus, follistatin-associated conditions include abnormal tissue growth and developmental defects.
(180) Exemplary conditions for treatment include neuromuscular disorders (e.g., muscular dystrophy and muscle atrophy), congestive obstructive pulmonary disease (and muscle wasting associated with COPD), muscle wasting syndrome, sarcopenia, and cachexia, adipose tissue disorders (e.g., obesity), type 2 diabetes (NIDDM, adult-onset diabetes), and bone degenerative disease (e.g., osteoporosis). Other exemplary conditions include musculodegenerative and neuromuscular disorders, tissue repair (e.g., wound healing), and neurodegenerative diseases (e.g., amyotrophic lateral sclerosis) (columns 66-67).
Kumar et al. teach that delivery can be via various routes including oral, systemic, implantation/subcutaneous, or injected to the target tissue (columns 71 and 72).
Kumar et al. tach delivery of FST288 or variants or truncations thereof. Kumar et al. teaches that the term “follistatin-related polypeptides” includes, for example, native follistatin, FLRG, WFIKKN1, and WFIKKN2 sequences, as well as variants and truncations thereof.
(18) The term “follistatin polypeptide” is used to refer to polypeptides comprising any naturally occurring polypeptide of the follistatin family as well as any variants thereof (including mutants, fragments, fusions, and peptidomimetic forms) that retain a useful activity, including, for example, ligand binding (e.g., myostatin, GDF11, activin A, activin B). For example, follistatin polypeptides include polypeptides comprising an amino acid sequence derived from the sequence of any known follistatin having a sequence at least about 80% identical to the sequence of a follistatin polypeptide
Kumar et al.t each that in addition, methods for making and testing libraries of polypeptides are described herein and such methods also pertain to making and testing variants of follistatin.
Kumar et al. teaches rinsing cells in phosphate-buffered saline and incorporation of glycerol. It would have been obvious as a matter of design choice to combine these agents that were each routinely used in the art at varying percentages.
Kumar et al. teaches that one or more follistatin-related fusion polypeptides, or combinations of such polypeptides of the disclosure can be administered concurrently with, prior to, or subsequent to, one or more other additional agents or supportive therapies.
Therefore, Kumar et al. teaches a method of administering FST288 or a variant thereof to treat sarcopenia or cancer cachexia (columns 66-67). Kumar et al. teaches that FST288 or a variant thereof can be used to treat or prevent muscle loss or decrease fat accumulation.
Since Kumar et al. teach that the composition can treat muscle wasting disorders or obesity, it would have been obvious for the person to require improvement in ambulatory activity, increase in endurance and sprinting activity, or to change in body composition comprising an increase in lean mass/fat ratio because these are normal desired improvements/parameters for obesity and/or muscle wasting.
Kumar et al. teach that each therapeutic agent will be administered at a dose and/or time schedule determined for that particular agent (column 71). Dosing and time schedule is considered to be a matter of design choice depending upon the condition and patient to be treated and is routine to one of skill in the art. Additionally, Krasney et al. (set forth below) teach that the dosage of the subject pharmaceutical compositions will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg. Krasney et al. teach that an effective dose or amount, and any possible effects on the timing of administration of the formulation, may need to be identified for any particular compound of the present invention. Krasney et al. teach that this may be accomplished by routine experimentation.
Kumar et al. teaches that FST288 sequence and a signal peptide, as set forth above, but does not teach the incorporation of tags.
However, Krasney et al. teach some mutant follistatins that act as selective myostatin inhibitors, as well as method of using them to treat muscle wasting disorders (abstract). Krasney et al. teach incorporation of GST-tags or His-tags as exemplary fusion proteins (page 7). It would have been obvious to incorporate these tags alone or in combination for the purpose of routine fusion protein design. Krasney et al. teaches that the benefits of fusion proteins include having a domain which increases its solubility and/or facilitates its purification, identification, detection, and/or delivery.
Krasney et al. teach follistatin mutants that inhibit myostatin, but have substantially reduced activin activity. These novel selective myostatin inhibitors may be administered to increase muscle mass in subjects in need thereof. Thus, the inhibitors may be useful for treating diseases where muscle wasting and/or weakness is a symptom. It is also possible that the inhibitors could be used to increase muscle in athletes. These mutants may also be effective in animals to increase muscle mass for strength, or to increase their food value. Thus, compositions comprising the mutants may be used as therapeutic agents for muscle wasting disorders or for enhancement of muscle mass in humans or animals.
Krasney et al. teach novel follistatin polypeptides and compositions thereof that are capable of stimulating muscle growth, as well as nucleic acids, vectors, host cells, etc. for expression and production of the same. Further, provided are novel methods of treating disorders where muscle wasting and/or weakness is a symptom, as well as novel methods of increasing muscle mass in a human subject or animal, using the follistatin polypeptides and compositions thereof, optionally in conjunction with other modes of therapy or stimulation, as well as kits for the practice of the same (page 2).
FIGURE 1 depicts domains of follistatin (FST) 288. Shown are the N-terminal domain (FSND) (SEQ ID NO: 1), three FST domains (FSDs) 1-3 (SEQ ID NOs: 2-4) aligned at their cysteine residues, along with the two FSDs of the FST homolog FSTL3 (SEQ ID NOs 5-6) and SPARC/BM40 (SEQ ID NO: 7) The sequences are divided to show the N-terminal (EGF-like) and C-terminal (Kazal-like) subdomains. Shaded bars denote the conserved hydrophobic residues used in mutational analyses. The heparin- binding sequence (FSD-I) is underlined.
Krasney et al. teach that they have been engaged in structure function studies of follistatin (FST) and as part of these studies, made a large number of mutants to determine which parts of the molecule were necessary for activin binding. We found that residues in the N-domain and second follistatin domain (FSD2), and to a lesser extent, residues in the first follistatin domain (FSDl) were important or critical for activin binding. We also made mutants in which the order of the follistatin domains was altered, or where individual domains were deleted and/or replaced by multiple copies of another domain. All of these domain mutants had vastly reduced or undetectable activin binding, except for those in which the third follistatin domain (FSD3) was deleted. Thus, mutating certain critical residues, or changing FSD order or content, vastly reduced or eliminated activin binding (page 4).
Krasney et al. teach that the present invention provides methods of stimulating muscle growth comprising administering the pharmaceutical composition to a subject. For example, stimulating muscle growth may be used to treat a subject that has a muscle wasting disorder. Accordingly, the present invention provides methods of treating a subject having a muscle wasting disorder comprising administering a pharmaceutical composition comprising a polypeptide or polynucleotide of the invention to a subject. In certain embodiments, the muscle wasting disorder is cancer. In other embodiments, the muscle wasting disorder is AIDS. In other embodiments, the muscle wasting disorder is sarcopenia. Such administration may be, for example, intrathecal, peripheral, systemic, or local.
Krasney et al. teach that the dosage of the subject pharmaceutical compositions will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
It would have been obvious in view of these teachings to deliver one or more dose of FST288 with a tag and one or more peptide sequences with a second tag with a reasonable expectation of treatment of the conditions taught by the prior art.
Yaden et al. teach that Follistatin is a novel therapeutic for the improvement of muscle regeneration (title) and teach that FST288 promotes slightly greater muscle anabolic effects than FST315 (page 357). Yaden et al. teach that FST288 increased muscle mass 37.5%, whereas FST315 increased muscle mass 23.7% (Fig. 1D). Altering the HBS region of FST288 (FST288-DHBS) significantly reduced the local activity of the protein, resulting in a 12.3% increase in muscle mass (page 357).
Response to Arguments
Contrary to applicant’s arguments, the combination of the references render the instant claims obvious. The references are not required to reduce the method to practice. Although applicant argues that the specifications are only hypothesis alone, without concrete evidence or a practical application, this is actually true regarding the instant specification.
Applicant argues that in vivo experiments were performed by systemic application of FST288 in mice and the experimental results are absolutely convincing to propose the systemic application of FST288 to a person in preventing/reversing multiple disease conditions (as claimed). The experimental study was comprehensive, manufacturing of FST288 has been standardized and the produced peptide experimentally described the change in muscle structure and function, change in body composition in terms of muscle/fat, and the change in body performances.
This assertion by applicant does not appear to be disclosed in the instant specification. The specification does not demonstrate delivery of FST288 and a tag with resultant treatment of sarcopenia or cancer cachexia.
Applicant argues that the protein complex as claimed by Kumar et al. does not match with FST288 as claimed in the current application. Contrary to applicant’s arguments, the instant claims do not recite any specific FST288, but rather recite any FST288. The instant claims are not directed to any specific FST288 or expression construct. Applicant is arguing limitations that are not claimed.
Applicant argues that Kumar et al. claimed a method for treating muscle-related disorder and in the specification described multiple disease conditions. It is not specified whether any combination of first and second polypeptide of the protein complex will cure all the disease conditions as mentioned, or a particular combination will cure a specific disease condition. The applicant of the current application considers that the artwork of Kumar et al. is nonspecific.
The teachings of Kumar et al. cited by the examiner fall within the instant claimed scope. The reference is considered as enabled as the instant specification.
Applicant argues that Krasney et al. (WO/2008/030367) claimed their composition as 'An isolated,