FINAL ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant’s correspondence filed June 30, 2026 is acknowledged; claim 1 has been amended to recite “the MST1R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC does not comprise 3:49684009:G:A.” Claims 2-11 and 14-44 are canceled; claims 45-48 are new. Claims 1, 12-13, and 45-48 are pending examination and currently under consideration for patentability.
Withdrawn Rejections
3. The rejection of claims 1 and 33 under 35 U.S.C. 102 (a)(1) and 102(a)(2) as being anticipated by Egen et al. (US20160032013A1, published February 4, 2016), is withdrawn in view of Applicant’s amendments and the cancellation of claim 33. See section 8 of the previous Office action.
Maintained Rejection
Claim Rejections - 35 USC § 112
4. 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.
Enablement
5. Claims 1, 12-13, and 45-48 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 enablement requirement. The claims contain 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.
Factors to be considered in determining whether a disclosure enables one skilled in the art to make and use the claimed invention in its full scope without resorting to undue experimentation include: (1) the quantity of experimentation necessary; (2) the amount of direction or guidance presented; (3) the presence or absence of working examples; (4) the nature or complexity of the invention; (5) the state of the prior art; (6) the relative skill of those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the claims. See In re Wands, 8 USPQ2d. 1400 (Fed. Cir. 1988).
In the instant case, the nature of the invention is complex and unpredictable, involving the effects of biological molecules on an individual having diseased physiology. As was found in Ex parte Hitzeman, 9 USPQ2d 1821 (BPAI 1987), a single embodiment may provide broad enablement in cases involving predictable factors such as mechanical or electrical elements, but more will be required in cases that involve unpredictable factors such as most chemical reactions and physiological activity. This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology", Mycogen Plant Sci., Inc. V. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970); Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991).
Specifically, the claimed invention is broadly directed to a method of treating a patient having inflammatory bowel disease (IBD) or primary sclerosing cholangitis (PSC), the method comprising administering to the patient an agonist of the Macrophage Stimulating 1 (MST1)/Macrophage Stimulating 1 Receptor (MST1R) pathway. The remaining species recited in the claims is agonist comprising “MST1 protein.” Dependent claims recite additional method steps of detecting the presence or absence of an MST1 and/or MST1R variant nucleic acid molecule or variant polypeptide associated with an increased risk of developing IBD and/or PSC. The claims are broad with respect to the agent being administered (agonist comprising genus “MST1 protein” with no additional structural limitations, which encompasses myriad MST1 fusion proteins having no support in the specification).
Conversely, the amount of detailed guidance and working examples provided by the application is decidedly narrower. The specification only demonstrates overexpression of MST1 by hydrodynamic delivery of expression construct comprising wild-type MST1 cDNA (i.e., Example 6), which is not equivalent to administering the protein directly as instantly claimed. However, the source of this agonist is not provided, nor are structures thereof other than wild-type MST1 (i.e., SEQ ID NO: 35). Accordingly, the ordinary skilled artisan is not taught how to make and use them within the entire scope of the claimed methods.
Furthermore, none of the potential therapeutic agents were tested for therapeutic activity in a patient, animal model, or in vitro. Six MST1R variants were shown to be associated with Crohn's Disease (a type of IBD) in Table 3. A prophetic example is provided about generating a mouse model of IBD wherein MST1R is knocked out (Example 2). However, the model was not generated and evaluated critically as a good or bad model of IBD. Also, no potential drugs were tested in the model. Example 3 provides data regarding two MST1 variants (rs3197999 and 3:49684379:G:A) that are been associated with increased risk of IBD and PSC, as well as reduced serum levels or activity of MST1. (Mutation rs3197999 is disclosed as being linked to IBD in Goyette et al., 2008, Mucosal Immunology 1(2):131-138; of record). Example 4 shows that induction of colitis in mice via administration of DSS resulted in increased expression of MST1 and MST1R. Human IBD, Crohn's, UC, and FGID subjects also had increased serum levels of MST1 and/or MST1R. Example 5 discloses generation of a variant MST1R construct. Example 6 postulates that increased MST1/MST1R signaling is protective and/or promotes tissue repair in IBD and PSC. The example discloses expression of WT and variant MST1 constructs in normal mice. Again, no effect on IBD and/or PSC was demonstrated.
The state of the art establishes that a correlation between altered expression or function of a protein (or its encoding gene) and a disease state may be of interest diagnostically, but does not automatically or predictably indicate that treatment with an agonist or antagonist of the altered protein (or gene encoding such) would be beneficial. Specifically, markers can be elevated as a result of the disease, or as part of a body's response to a disease, and cannot be presumed to be causative or contributory to the disease without significant further research. For example, with respect to G-protein coupled receptor perturbations in the disease hypertension, "it has been difficult to determine whether they are the cause or consequence of the disease" (Feldman, 2002, Molecular Pharmacology. 61(4): 707-709; of record). With respect to temporal lobe epilepsy, Janigro (2008, Epilepsy Currents 8(1): 23-24) teaches that "[a]s with many pathological findings in neurodegenerative diseases, it is difficult to determine if the changes are a cause or consequence of epileptic seizures" (p. 23). The literature also speaks to GDF15 levels and cardiac disease, For example, Kempf et al. (2007, Clin. Chem. 53:284-291; of record) and Kempf et al. (2006, Cir. Res. 98:351-360; of record) show a correlation between elevated that GDF-15 levels and adverse cardiovascular events. Such may suggest that treatment with anti-GDF-15 would be beneficial to patients, as was postulated by US 7,919,084 (Breit et al., issued 05 April 2011; of record). However, it was also hypothesized that GDF-15 expression was elevated in response to the cardiovascular event as a way for the body to attempt to protect its tissues from ischemia/reperfusion injury, and data in support of this hypothesis were sound. See Xu et al. (2006, Circ. Res. 98:342-350); Tobin et al. (2006, Drug Discovery Today 11:405-411; of record); and Lajer et al. (2010, Diabetes Care 33:1567-1572; of record). In light of the contradictory findings in the prior art, the therapeutic effects of administering a MST1 or MST1R agonist to a subject—let alone genus “MST1 protein”—could not have been predicted without significant further research amounting to an act of further invention. Accordingly, discovery of a correlation alone is not enabling for a method of treatment.
Additionally, regarding the remaining recited therapeutic agent, the scientific literature provides evidence that significant optimization and undue experimentation is required to create an effective therapeutic “protein” as instantly claimed. For example, Binder et al. ("Strategies for extending the half-life of biotherapeutics: successes and complications." Expert Opinion on Biological Therapy 25.1 (2025): 93-118) shows that therapeutic proteins are often rapidly cleared from the subject’s body, and so additional modifications to the protein, requiring substantial trial and error to perfect, are typically required to generate a workable protein therapeutic. Goswami et al. ("Gene therapy leaves a vicious cycle." Frontiers in oncology 9 (2019): 297) summarizes the undue experimentation required well: “more than 5,000 critical steps are involved in developing a single therapeutic protein. Therefore, the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source.” Goswami et al. at introduction.
Due to the large quantity of experimentation necessary to determine how to achieve a desired therapeutic effect on IBD and/or PSC via administration of a MST1 and/or MST1R agonist comprising “MST1 protein,” the lack of direction/guidance presented in the specification regarding the same, the absence of working examples directed to the same, the complex nature of the invention, the state of the prior art establishing the unpredictability of the effects of a drug targeted to a marker of a disease, and the breadth of the claims, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Applicant’s Arguments:
Applicant urges that a person skilled in the art would be able to practice the claimed subject matter without being required to perform undue experimentation. Applicant argues: a. the nature of the claimed subject matter; b. the state of the art; c. the level of skill in the art; d. the level of predictability; e. the amount of direction that the subject application provides; f. the present Application’s effective disclosure of a working example; and g. the limited amount of experimentation required to make and use the claimed subject matter—all favor Applicant’s position and therefore there is no reason to believe that a person skilled in the art would have been required to perform undue experimentation to make and use the claimed subject matter.
A. Applicant urges the nature of the claimed subject matter favors Applicant’s position. Applicant alleges: that the Office improperly made no finding of fact as to the nature or complexity of the invention; and citing the MPEP, that “[t]he fact that experimentation may be complex does not necessarily make it undue, if the art typically engages in such experimentation.”
B. Applicant urges the state of the art favors Applicant’s position. Applicant alleges: that Feldman, Janigro, and Kempf—cited in the rejection of record to characterize the state of the art of treating diseases with a protein based on detecting altered expression or activity of the protein—are not relevant to Applicant’s claims because the cited references are not directed to IBD or PSC; and that Binder and Goswami—cited in the rejection of record to establish that gene therapies are distinct from protein therapeutics and that development of protein therapeutics requires substantial experimentation—are not relevant because, citing the MPEP “it is not necessary to enable one of ordinary skill in the art to make and use a perfected, commercially viable embodiment absent a claim to that effect,” and because administering therapeutic proteins is allegedly a mature endeavor, as evidenced by the 1923 Nobel prize for the discovery of insulin.
C. Applicant urges the level of skill in the art favors Applicant’s position. Applicant alleges: the level of skill in the art is such that a person skilled in the art with the benefit of Applicant’s disclosure (but not without) could have made and used the claimed subject matter; and that the Office improperly made no finding of fact as to the level of skill in the art, and therefore the Office has not met the initial burden to question enablement of the claimed subject matter based on the level of skill in the art.
D. Applicant urges the level of predictability in the art favors Applicant’s position. Applicant alleges: the Office’s citation to the Amgen case—to characterize the level of unpredictability in the art—lacks relevance because the patents in Amgen issued in 1987, and the state of the art for a given technology is not static in time; that the Office’s citation to the Ex parte Hitzeman case—to establish more than a single embodiment is required to provide enablement in most biotechnology applications—lacks relevance in view the instant applicant’s Declaration and the breadth of the disclosure in instant specification (summarized by Applicant); and that the Office’s citation to the Mycogen Plant Science case—to establish the instant applicant falls into the class of subject matter the Federal Circuit has characterized as unpredictable— lacks relevance because the case has dicta stating “simultaneous conception and reduction to practice is somewhat rare but certainly not unknown” and the case was decided under 35 U.S.C. 102(g) grounds.
E. Applicant urges the amount of direction that the subject application provides favors Applicant’s position. Applicant alleges: the specification’s failure to disclose administration of a MST1 protein is cured by the specification’s disclosure of species, symptoms, and pathology of IBD/PSC, methods of administration, and agonists of the MST1/MST1R pathway—because, citing the MPEP “[t]he specification need not disclose what is well-known to those skilled in the art and preferably omits that which is well-known to those skilled and already available to the public.”
F. Applicant urges the present application’s effective disclosure of a working example favors Applicant’s position. Applicant alleges: the specification’s failure to demonstrate actual treatment of IBD and/or PSC is cured by the remainder of the specification’s disclosure and the Declaration. Applicant submits the specification’s disclosure and the declaration amounts a working example (Applicant points to specification predicting MST1 transgenic mice will be protected in mouse models of IBD) and notes that the MPEP teaches “[c]ompliance with the enablement requirement…does not turn on whether an example is disclosed.”
G. Applicant urges the limited amount of experimentation required to make and use the claimed subject matter favors Applicant’s position. Applicant alleges: the Office’s conclusion that “a large quantity of experimentation [is] necessary to determine how to achieve the desired therapeutic effect on IBD and/or PSC via administration of a MST1 and/or MST1R agonist” is an improper conclusory statement because: the Office made no findings of fact in this regard. Therefore, the Office allegedly has not met the initial burden to question enablement of the claimed subject matter based on the amount of experimentation required to make or use the claimed subject matter.
Response to Arguments:
Applicant’s arguments have been carefully considered but are not deemed persuasive.
A. The claims are drawn to a method of treating a patient having inflammatory bowel disease (IBD) or primary sclerosing cholangitis (PSC), the method comprising administering to the patient an agonist of the Macrophage Stimulating 1 (MST1)/Macrophage Stimulating 1 Receptor (MST1R) pathway, wherein: the agonist of the MST1/MST1R pathway comprises an MST1 protein; the patient has been determined to be heterozygous or homozygous for an MST1 and/or MST1R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC; and the MST1R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC does not comprise 3:49684099:G:A according to GRCh38/hg38 assembly coordinates. In response to Applicant’s argument regarding the nature of the invention, the instant disclosure is not enabling because: if fails to show how to make and use the instantly claimed genus of MST1 proteins. There is no disclosure of treatment of IBD and/or PSC with any MST1 proteins in the instant specification or the Declaration of Dr. Horowitz filed December 8, 2022. The invention is in the same class of invention which the CAFC has characterized as unpredictable. These are the Office’s finding of fact.
B. The cited references are relevant to Applicant’s claims. Feldman, Janigro, and Kempf were cited by the Examiner as a general teaching to characterize the state of the art of treating diseases with a protein based on detecting altered expression or activity of the protein; that is, it is generally unpredictable if altered expression or activity of a protein is a cause or consequence of any particular disease, and therefore, how the disease may be treated by administering the protein. Applicant has demonstrated that MST1/R variants correlate with IBD and/or PSC; not that MST1/R variants cause IBD and/or PSC and furthermore treatable with MST1 protein. For example, there is no disclosure of treatment of IBD and/or PSC with any MST1 proteins in the instant specification; and the Declaration filed December 8, 2022 discloses a gene therapy that is not commensurate in scope with the instantly claimed MST1 protein therapeutic.
Binder and Goswami are cited to convey that the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source. Goswami at introduction.
C. It should be noted that the Office has made a proper assessment to question of enablement of the regarding the claimed invention based on Wand factors and the evidence as a whole. The MPEP instructs: “[w]hile the analysis and conclusion of a lack of enablement are based on the factors discussed in MPEP § 2164.01(a) and the evidence as a whole, it is not necessary to discuss each factor in the enablement rejection.” See MPEP section 2164.04.
D. Applicant’s assertion about the Ex parte Hitzeman case lacks relevance because: the instant application has not disclosed even a single embodiment using a protein therapeutic as instantly claimed—let alone more than one embodiment as contemplated by Ex parte Hitzeman. The MPEP also indicates that Amgen is still highly relevant to biotechnology applications, such as the instant application. See e.g., MPEP at section 2164.08.
E. Applicant has not disclosed a single therapeutic MST1 protein. For example, “more than 5,000 critical steps are involved in developing a single therapeutic protein. Therefore, the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source.” Goswami at introduction. Contrary to Applicant’s assertion, therapeutic MST1 proteins are not well known in the art, nor ascertainable from the instant specification. Applicant has not defined the structure of the MST1 proteins for use in the claimed invention, and therefore has not taught any person skilled in the art how to make and use the instantly claimed MST1 proteins. Applicant has demonstrated in vivo expression of WT MST1 protein by nucleic acids, however, that is not equivalent to the protein therapeutic instantly claimed.
F. The declaration filed on December 8, 2022 is insufficient to overcome the rejection as indicated in the previous office action. It would be undue experimentation to practice the claimed invention in view of specification’s disclosure and the declaration filed December 8, 2022. The instant claims are directed to a method of treating a patient already having IBD or PSC, whereas the declaration concerns experiments showing a degree of protection against development of IBD in a model. Accordingly, the preventative experiments disclosed in the declaration are not probative of enablement of the instantly claimed method of treating ill subjects. The instant claims also recite treatment with an “MST1 protein” without reciting any structural limitations therefor. In contrast, the experiments described in the Declaration filed December 8, 2022 are limited to pre-treatment with a nucleic acid encoding murine WT MST1. Such is not commensurate in scope with the claims, which are directed to directly administering a MST1 protein therapeutic. The declaration dated December 8, 2022 is therefore insufficient to show enablement of the claimed invention because (i) no MST1 protein therapeutic is demonstrated, and (ii) prevention is demonstrated, not treating an ill subject. Therefore, it would be undue experimentation for the skilled person to practice the claimed invention because the skilled person would need to not only develop the nucleic acid therapy demonstrated in the Declaration filed December 8, 2022 into a protein therapy, but then also test if it could treat subjects having IBD and/or PSC. Such experimentation amounts to undue experimentation at least because the quotient of unpredictability is very high in developing protein therapeutics, as discussed by Goswami.
G. The Office’s conclusion that “a large quantity of experimentation [is] necessary to determine how to achieve the desired therapeutic effect on IBD and/or PSC via administration of a MST1 and/or MST1R agonist” is not an improper conclusory statement at least because: “more than 5,000 critical steps are involved in developing a single therapeutic protein. Therefore, the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source.” Goswami at introduction. The Office therefore has met the initial burden to question enablement of the claimed subject matter based on the amount of experimentation required to make or use the claimed subject matter. The instant application lacks enablement for the MST1 protein therapeutics as instantly claimed.
Claim Rejections - 35 USC § 112
6. 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
7. Claims 1, 12-13, and 45-48 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 claims contain 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.
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.)
The claims are drawn to methods of treating a patient having IBD or PSC comprising administering a MST1/MST1R pathway agonist comprising “MST1 protein,” wherein the patient has a MST1 and/or MST1R variant associated with increased risk of developing IBD and/or PSC. The dependent claims recite various MST1 and MST1R variants related to IBD and/or PSC.
The claimed agonist comprising genus “MST1 protein” must possess specific functions, including treating IBD or PSC. There is no structure presented that corelates with this function. The specification only sets forth protein expression constructs having nucleotides encoding wild-type MST1 (i.e., SEQ ID NO: 35) as potentially having the required function, but the expression construct is not representative of the genus of agonists comprising “MST1 protein” instantly claimed.
Applicant is also not in possession of the breadth of subject populations treatable by species “MST1 protein” recited in instant claim 1.
A. No Written Description for agonists comprising genus “MST1 protein”
The claimed invention recites “wherein the agonist of the MST1/MST1R pathway comprises MST1 protein,” and the broadest reasonable interpretation for this recitation is: the claim language reads on directly administering not only wild-type MST1 protein (i.e., SEQ ID NO: 35), but also fusion proteins comprising the wild-type MST1 protein. The specification also indicates “MST1 protein” includes fusion proteins comprising the MST1 protein, and fragments thereof. However, the specification only discloses administering an expression construct comprising cDNA encoding wild-type MST1 protein (i.e., Example 6), as set out below.
Example 6 shows: “Hydrodynamic delivery (HDD) was used to deliver WT MST1 cDNA packaged in an expression construct to mice, leading to overexpression of WT MST1. Mice injected with MST1 HDD construct survived the course of experiment, indicating that MST1 overexpression is not lethal (data not shown).” Specification at page 36, lines 9-12. No other agonists of the MST1/MST1R pathway are administered in the specification, let alone administration of members of the genus “MST1 protein”.
The specification teaches regarding MST1 protein: “In some embodiments, the MST1 agonist is a protein, such as recombinant MST1. In some embodiments, the recombinant MST1 is a fusion protein comprising MST1 or a fragment thereof fused to a heterologous protein, for example an antibody or a fragment thereof, such as Fc fragment (e.g., Mst1-Fc).” Specification at page 13, lines 9-13.
The (i) broadest reasonable interpretation of the claim-recited term “MST1 protein,” and (ii) the specification, suggests that “MST1 protein” encompasses an unbounded genus MST1 fusion proteins, but the specification does not define any structural features commonly possessed by the member of the genus. The claims recite functional language of the proteins, such as that the proteins treat IBD and PSC, however a definition by function does not suffice to define the genus because it is only an indication of what the protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of MST1 protein is highly variable (i.e., each MST1 protein would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed MST1 proteins have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art regarding the unpredictability of fusion proteins, e.g., Fc fusions, is made herein.
Binder et al. ("Strategies for extending the half-life of biotherapeutics: successes and complications." Expert Opinion on Biological Therapy 25.1 (2025): 93-118), teaches that many therapeutic proteins have short half-lives when administered directly and that Fc fusion proteins can extend half-life. Binder et al. at Table 1. Regarding Fc fusion technology, Binder et al. teaches that Fc and linker selection/optimization is critical to preserving the activity of the protein: “[a] critical component of Fc fusion proteins is the linker, which can significantly affect the binding activity of the fusion partner, as shown for dulaglutide (Trulicity®)[… .] Whereas fusion of the GLP-1 derivative via the natural hinge region to an IgG1 Fc reduced potency in vitro by 95% in comparison to the free peptide, optimization of linker length and sequence, together with the choice of an Fc from the IgG4 subclass, led to a four-fold improvement.” Binder et al. at page 104, right col. In other words, a person of skill in the art would readily appreciate that significant unpredictability exists around how to construct Fc fusion proteins suitable as therapeutics. No MST1 fusion proteins are provided in the specification, let alone MST1-Fc fusion proteins and/or fusion proteins comprising fragments of MST1. Therefore, neither the art nor the specification provides a sufficient representative number of MST1 proteins that are therapeutically effective to meet the written description requirement for instant claims directed to the genus “MST1 protein.”
The claims also lack written description for administering the species unmodified “MST1 protein,” e.g., SEQ ID NO: 35. The specification only discloses administering an expression construct comprising WT MST1 cDNA via hydrodynamic delivery, not administering the protein directly. To address this issue, a further brief assessment of the art regarding challenges with converting gene therapies to protein therapies is made herein.
Binder et al. further teaches that “[e]ngineering of the drug half-life in vivo has become an integral part of modern biopharmaceutical development due to the fact that many proteins/peptides with therapeutic potential are quickly cleared by kidney filtration after injection and, thus, circulate only a few hours in humans (or just minutes in mice).” Binder et al. at Abstract. Binder et al. teaches therapeutic effects are unlikely by administering an unmodified therapeutic protein, as presently encompassed by the claims, e.g., “[c]ompared to the unmodified protein/peptide, the concentration of the [modified] drug with prolonged plasma half-life remains much longer within the therapeutic window. This cannot be achieved by higher dosing [of the unmodified protein], which poses the risk of eliciting side effects[.]” Binder et al. at FIG. 2. Various techniques to extend half-life have been successfully applied to different proteins, e.g., PEGylation, FC fusion, hyper glycosylation, albumin fusion, and lipidation. Binder et al. at Table 1. However, significant research and development is required to obtain a solution that extends the half-life while retaining the functionality of the protein; it is unpredictable what modification will work. For example, regarding possible PEGylation solutions: “examples underline that there is no universal plug-and-play solution for PEGylation of biopharmaceuticals. Rather, the coupling chemistry, choice of linker, type of PEG macromolecule – branched, linear, short or long chain – and the conjugation site(s) within the pharmacologically active protein or peptide must be optimized individually[.]” Binder et al. at page 98, left col.
Goswami et al. ("Gene therapy leaves a vicious cycle." Frontiers in oncology 9 (2019): 297) summarizes the unpredictability of converting the hydrodynamic delivery of an expression construct expressing MST1 demonstrated in the specification to the protein therapy instant claimed well: “more than 5,000 critical steps are involved in developing a single therapeutic protein. Therefore, the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source.” Goswami et al. at introduction. Therefore, neither the art nor the specification provides a sufficient number of MST1 proteins suitable as therapeutic proteins to meet the written description requirement for instant claims directed to the species unmodified “MST1 protein.”
It is therefore unknow how either the species unmodified “MST1 protein” or the genus “MST1 protein” in general would work for treating IBD or PSC, especially considering the specification provides no examples of treating any disease, let alone IBD or PSC, with any MST1R agonist. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore proves insufficient written description to support the “MST1 proteins” encompassed by the claims. Given all the above, Applicant does not have written description for MST1 protein.
B. No Written Description for Breadth of Genus: “Patient Heterozygous or Homozygous for an MST1 and/or MST1R Variant Nucleic Acid Molecule Associated with an Increased Risk of Developing IBD and/or PSC.”
Claim 1 also recites treating a patient of the genus “heterozygous of homozygous for an MST1 and/or MST1R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC.” Dependent claims 12-13 and 33-14 further specify species of MST1 and MST1R variants associated with the risk of developing IBD and/or PSC. Claim 1 is therefore very broad as to MST1 and MST1R variants associated with increased risk of developing IBD and/or PSC that may be treatable with the claimed invention; however, Applicant has only demonstrated possession of the variants included in the dependent claims. Additionally, Egen et al. (US20160032013A1, published February 4, 2016) discloses the treatment of a patient heterozygous or homozygous for MST1 variant rs3197999 with MST1 protein agonist. See e.g., Egen et al. at para. [0004]. Therefore, Applicant is not in possession of the breadth of subject populations treatable by species “MST1 protein” recited in instant claim 1.
The cited references therefore demonstrate that the treatment of IBD or PSC with an “MST1 protein” is highly unpredictable, if even possible.
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:
A. Applicant urges the specification fully supports the claim language “the agonist of the MST1/MST1R pathway comprises an MST1 protein.” Applicant alleges: the Office’s conclusion that the MST1 proteins recited in the claims have no correlation between their structure and function is mistaken because: there was no need for a detailed description of a genus of MST1 variant proteins in the specification of the present application. Applicant urges that a skilled artisan would have been able to identify species of MST1 variant proteins by e.g., employing common tools, therefore there was no need for a detailed description of a genus of such variant proteins in Applicant’s specification.
B. Applicant urges the specification fully supports the claim language “an MST1 and/or MST1R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC.” Applicant alleges: the Office’s conclusion that Applicant has only demonstrated possession of the variants included in the dependent claims is mistaken because: there was no need for a detailed description of a genus of MST1 and/or MST1R variant nucleic acid molecules associated with an increased risk of developing IBD and/or PSC in the specification of the present application; Applicant submits such species were well known in the art as of the earliest effective filing date as evidenced by the variant excluded from presently amended claim 1; that a skilled artisan would have been able to identify species of MST1 variant nucleic acid molecules by e.g., employing common tools such as NCBI to identify additional variants, and therefore there was no need for a detailed description of a genus of such variant nucleic acid molecules in Applicant’s specification. Applicant cites the Ajinomoto Co. case (“a skilled artisan ‘would have been able to identify more potent promoters by employing common tools for measuring RNA transcription’”) and the MPEP (“[i]nformation which is well known in the art need not be described in detail in [Applicant’s] specification”) to support the proposition that MST1 and/or MST1R variant nucleic acid molecules associated with an increased risk of developing IBD and/or PSC are readily identifiable using common tools, therefore the variant nucleic acid molecules are well known and need not be described in detail in the specification.
Response to Arguments:
Applicant’s arguments have been carefully considered but are not deemed persuasive.
A. For clarification, the instant claims recite that the agonist of the MST1/MST1R pathways comprises an MST1 protein, not an MST1 variant protein. The claims further recite MST1/R variant nucleic acid molecules for determining the treatment subject population, said variants associated with risk of developing IBD/PSC. Therefore, Applicant’s assertion that: there was no need for a detailed description of MST1 variant proteins is not found persuasive because: the subject rejection was directed to a need for description of the structure of MST1 therapeutic proteins.
The claimed agonist comprising genus “MST1 protein” must possess specific functions, including treating IBD or PSC. There is no structure presented that corelates with this function. The specification and Declaration filed December 8, 2022 only sets forth expression constructs having nucleotides encoding WT MST1 as potentially having the required function, but the expression constructs are not at all representative of the genus of agonists comprising “MST1 protein” instantly claimed. For example, the Declaration utilized a powerful rAAV8 gene therapy that results in a continuous overexpression of the MST1 protein. See Declaration filed December 8, 2022 at para. 4. Such a technology is not sufficient to establish possession of the MST1 protein therapeutic instantly claimed.
The claims recite functional language of the proteins, such as that the proteins treat IBD and PSC, however a definition by function does not suffice to define the genus because it is only an indication of what the protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of MST1 protein is highly variable (i.e., each MST1 protein would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed MST1 proteins have no correlation between their structure and function.
The specification and declaration filed December 8, 2022 present no MST1 protein therapeutics, and so a person of skill in the art would therefore need to develop said therapeutic MST1 protein. Said therapeutic protein would need to be modified to have e.g., appropriate half-life to treat the disease, as discussed by Binder. Applicant has not demonstrated possession of any said (therapeutic) MST1 proteins.
For example, “more than 5,000 critical steps are involved in developing a single therapeutic protein. Therefore, the quotient of unpredictability is very high in developing both chemical and protein-based therapies. Gene therapy, on the other hand, leads to long-lasting production of the desired therapeutic protein and can localize protein expression to an area of the body, fixing the problem at its source.” Goswami at introduction.
Not even a single MST1 protein therapeutic is disclosed by the instant disclosure. Applicant has not presented that they were in position of a method of administering MST1 protein therapy by the instant disclosure. For example, the Declaration may show that applicant was in possession of administering MST1 gene therapy, but this is insufficient to establish possession of administering MST1 therapeutic proteins directly, as instantly claimed, because: gene therapy to overexpress a WT protein is a substantially different and more powerful solution than directly administering a WT protein having no further modifications. Accordingly, a disclosure of MST1/R variant nucleic acid molecules and MST1 gene therapies does not cure the written description deficiency for instant claims directed to MST1 protein therapeutics.
B. Instant claim 1 is very broad because it encompasses subject populations having any MST1/R variant nucleic acid molecule associated with an increased risk of developing IBD and/or PSC (other than the prior art variant presently excluded from the claim). The six variants Applicant demonstrates in the specification, and Applicant has possession for, are recited in dependent claim 13.
The claims recite functional language of the MST1/R variant nucleic acids, such as that they associate with an increased risk of developing IBD and/or PSC, however a definition by function does not suffice to define the genus because it is only an indication of what the MST1/R variant nucleic acid does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of MST1/R variant nucleic acids is highly variable (i.e., each MST1/R variant nucleic acid would necessarily have a unique structure; see MPEP 2434), the generic description of the nucleic acids is insufficient to describe the genus. Thus, the encompassed MST1/R variant nucleic acids have no correlation between their structure and function.
Applicant’s assertion that: MST1 and/or MST1R variant nucleic acid molecules are readily identifiable using common tools, and therefore the variant nucleic acid molecules are well known and need not be described in detail in the specification is not found persuasive because: written description / possession is determined at the time the claimed-invention was filed, and therefore cannot be based on databases later populated with additional species of the claimed-invention. See e.g., MPEP at section 1261.01 (“[a] written description requirement issue generally involves the question of whether the subject matter of a claim is supported by [conforms to] the disclosure of an application as filed. If the examiner concludes that the claimed subject matter is not supported [described] in an application as filed, this would result in a rejection of the claim on the ground of a lack of written description under 35 U.S.C. 112(a)”).
One of skill in the art cannot look to the present-day state of the art to fill the gaps in the instant disclosure. There is nothing of record in this application to suggest any MST1/R variant nucleic acid molecules other than the species recited in the claims were known, and let alone known to be associated with an increased risk of developing IBD and/or PSC. Applicant therefore only has possession of the variant nucleic acid molecules recited at instant claim 13, and not the broad genus of variant nucleic acid molecules presently recited at instant claim 1.
Conclusion
8. No claim is allowed.
9. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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