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 .
Amendments
In the reply filed 9/2/2025, Applicant has amended Claims 1, 3, 6 and 11, and cancelled Claim 4.
Claims 2, 5, 8, 10, and 22-24 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 3, 6, 7, 9, 11, 13, and 14 are under consideration.
Election/Restrictions
Applicant’s election of the following species without traverse in the reply filed on 1/21/2025 has been acknowledged.
Compound that binds, associates, or interacts with the TrxG-MLL complex.
Withdrawn Claim Objections
The objections to Claims 1 and 6 have been withdrawn due to Applicant’s amendment.
Maintained Claim Rejections - 35 USC § 112(a)
(Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 6, 7, 9, 11, 13, and 14 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 claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of methods for treating and/or preventing diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that interferes with, prevents or inhibits binding between R2R1 with TrxG-MLL and/or a component or subunit thereof. As discussed supra, the specification fails to describe the genus of methods and would require undue experimentation to discover these methods.
Independent claim 1 encompass a genus of methods for treating and/or preventing diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that interferes with, prevents or inhibits binding between R2R1 with TrxG-MLL and/or a component or subunit thereof.
In regard to the genus of compounds encompassed by the claimed methods, Applicant’s compounds include nucleic acids, antisense oligonucleotides, carbohydrates, proteins, peptides, small molecules that interfere with the TrxG-MLL complex, and antibodies (including antigen binding or target binding fragments thereof) capable of interfering with, blocking or neutralizing binding of R2R1 to the TrxG-MLL complex p. 6, 1st para., p. 10, last para.to p. 12, 2nd para. of Applicant’s specification. However, Applicant’s disclosure has not demonstrated nor described a compound that treated a subject with any of the claimed diseases and/or conditions.
Dependent claims 3, 9, and 11 encompass a genus of compounds that bind to or associate with the R2R1 binding sites within the TrxG-MLL complex, which are further limited to compounds that interfere with, prevent or inhibit binding between R2R1 and the TrxG-MLL complex, which are further limited to R2R1 proteins and peptides, and neutralizing antibodies. However, Applicant’s disclosure has not demonstrated nor described the binding sites between R2R1 and the TrxG-MLL complex, nor any compound, peptide, or antibody that is capable of interfering with, preventing, or inhibiting the interaction.
Dependent claim 7 encompass a genus of compounds that bind, associate or interact with the TrxG-MLL complex, which are further limited to include nucleic acids, antisense oligonucleotides, carbohydrates, proteins, peptides, small molecules, and antibodies including antigen binding or target binding fragments thereof. However, Applicant’s disclosure has not demonstrated nor described any these compounds that bind, associate or interact with the TrxG-MLL complex, and are capable of achieving the claimed method.
Dependent claims 13 and 14 encompass a genus of diseases and/or conditions associated with aberrant or defective ciliogenesis to be treated and/or prevented, which are limited to ciliopathies such as COPD. However, Applicant’s disclosure has not demonstrated nor described a subject with any of the claimed ciliopathies that was treated by the claimed method.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature 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. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for methods of treating and/or preventing a pulmonary and/or airways disease and/or condition caused with aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex, and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex. The absence of working examples directed to this genus of methods necessitates further experimentation. Additionally, no working examples were provided that utilize a cell culture system representative of a disease and/or condition associated with aberrant or defective ciliogenesis by administering to a compound that binds, associates, or interacts with the TrxG-MLL complex, and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex. Therefore, the specification does not provide sufficient guidance on how to practice the claimed method.
In regard to instant claims encompassing a genus of methods for treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex, Applicant describes the TrxG-MLL complex as a multi-subunit protein complex comprising the core members TrxG and MLL, as well as associated members DPY-30 and ASH2L, which maintain active gene expression by histone H3 lysine K4 methylation. However, Applicant has not demonstrated nor described a compound that binds, associates, or interacts with the TrxG, MLL, DPY-30 or ASH2L, that is capable of interfering with, preventing, or inhibiting binding between R2R1 thereby treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis complex.
By contrast, what Applicant’s has attempted to demonstrate and describe is a protein/protein interaction between R2R1 (alias FAM25C) and the DPY-30 and ASH2L members of the TrxG-MLL complex, and has attempted to extrapolate that because shRNA inhibition of the R2R1 gene in primary bronchial epithelial cells (PBEC) upreguates genes associated with ciliogenesis and/or cilary movement which are also involved with COPD (Figures 3-9, 13-18 of the disclosure), and appears to increase number of ciliated PBECs from both normal and COPD patients (Figures 22 and 23), this supports a method of treating and/or preventing diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis in a subject by administering any compound that binds, associates or interacts with the TrxG-MLL complex, that interferes with, prevents, or inhibits binding between R2R1 with the TrxG-MLL complex.
In light of this limited disclosure, Applicant’s claimed genus of methods suffer from a lack of enablement on at least two grounds.
First, neither Applicant’s disclosure nor the prior art (see more below) disclose that either TrxG, MLL, ASH2L, or DPY-30 can regulated ciliogenesis, much less be generically targeted by a genus of compounds that interfere with, prevent, or disrupt R2R1 binding in order to treat and/or prevent a pulmonary and/or airway disease or condition of ciliogenesis.
Second, neither Applicant’s disclosure nor the prior art (see more below) sufficiently disclose or sufficiently describe the interaction between R2R1 and the TrxG-MLL complex that would allow one of ordinary skill to predictably make and use a compound which binds, associates or interacts with the TrxG-MLL complex so as to allow the treatment and/or prevention of a disease or condition of ciliogenesis. Specifically, Applicant has indicated that by a yeast two hybrid screen that R2R1 was capable of interacting with DPY-30 (1/7 hits, data not shown) (p. 21, 3rd para.). Applicant goes on to demonstrated that when HA-tagged R2R1 is mixed in vitro with members of the TrxG-MLL complex, the anti-HA R2R1 can co-immunprecipitate ASH2L and perhaps DPY-30 (Fig. 2, p. 22, 2nd para.).
However, Applicant has not characterized this putative interaction in cells or in vivo, in order to establish that such an interaction would predictably occur in a subject.
Furthermore, Applicant has not identified the functional effects of the putative R2R1 binding on TrxG-MLL activity, in order to establish that such an interaction would predictably affect methyltransferase activity and/or is responsible for the observed effects of R2R1 on aberrant or defective ciliogenesis.
Finally, Applicant has not provided sufficient guidance for the making and using a compound that binds to or associates with R2R1 binding sites within the TrxG-MLL complex such that it can achieve the claimed function.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that methods for treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex so as to interfere with, prevent or inhibit binding between R2R1 is not a highly successful technique or has highly variable results. Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in practicing the instant invention.
Although the TrxG-MLL complex comprising components such as ASH2L and DPY-30 was known in the prior art for controlling histone methylation, it was not known to be involved in conditions associated with aberrant or defective ciliogenesis. Specifically, the prior art of Veazy et al. (Alc Res:Current Reviews, 2013;35(1):77-85) reviews the role of the TrxG-MLL complex with respect to general histone modification and epigenetic regulation (see Fig. 3 below), and teaches MLL was originally identified as playing a role in the development of different types of leukemia, but admits “very little information exists on individual TrxG proteins or their biochemical functions” (p. 82, 1st para.)
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Veazy states that the complex is thought to promote cell-specific patterns of gene expression by regulating global and gene-specific H3K4 methylation during early embryonic development as evidenced from MLL mouse gene knockouts, and that the proper functioning of TrxG complexes is indispensable to converting bivalent loci into an actively transcribed state required for neurogenesis, yet “much remains unknown regarding the temporal and tissue-specific regulatory evens these protein promote” (p. 83, 1st & 2nd para.). Thus, the prior art does not predict or reasonably suggest a compound that binds, associates, or interacts with the TrxG-MLL complex so as to interfere with, prevent or inhibit binding between R2R1 that could predictably treat and/or prevent a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis.
In regard to the interaction between R2R1 and members of the TrxG-MLL complex, the prior art is silent with respect to such an interaction. Furthermore, based on other known protein interactions with the TrxG-MLL complex, the in vitro binding data provided by Applicant’s Fig. 2 does not provide an enabling disclosure for making and using a compound that binds, associates or interacts with the TrxG-MLL complex, nor compounds that interfer with, prevent or inhibit the binding of R2R1 to achieve the claimed function effects. Specifically, the prior art of Ullius et al. (Nuc Acid Res, 2014, 42(11)6901-6020), see IDS filed 7/02/2021) demonstrated in vitro binding between MYC and ASH2L, but could not effect methyltransferase activity of the TrxG-MLL complex by deleting the in vitro interaction domain between ASH2L and MYC (p. 6906, col 2). Thus, the prior art indicates that making and using a compound that interferes with, prevents or inhibits binding between R2R1 and a member of the TrxG-MLL complex was not predictable and would have required undue experimentation.
Moreover, even with modern screening techniques, the generation of such compounds capable of the claimed function based on the limited disclosure by the Applicant was not predictable. Specifically, the prior art of Arkin et al. (Assay Guidance Manual, 2012, Eli Lilly & Co) teaches that is has been difficult to identify small molecules, antibodies or peptide inhibitors of protein-protein interactions (PPI). Often sited reasons for this challenge include a) the flat nature of PPI interfaces, which sometimes lack deep grooves where small molecules can stick, b) large contact area at the interface, which often exceeds the surface area of a drug-sized molecule, and c) bias in the screening libraries (p. 1, Introduction). Arkin goes on to state that even with modern screening formats, the screening for PPI inhibitors can identify compounds with many mechanisms of inhibition, some of which are undesired, such as direct assay interference, nonspecific binding, and covalent modification. Moreover, PPI screens must be optimized for the used of detergents, because no one detergent removes all aggregates, as well as for the sensitivity to diluting compounds such as DMSO, and necessitate multiple orthogonal assays because compounds will interfere with assays in multiple ways, some of which are difficult to predict (pgs. 2-3, General Considerations). Finally, Arkin discloses that although a primary screen may produce a set of compounds that might be active, many of these compounds will not be optimizable into a qualified drug that can be used in a subject. Moreover, the screens suffer from artifactual mechanisms that lead to activity in the primary assay, but do not translate into in vivo activity. A well-described and very common example is compound aggregation, which can interfere with protein structure in a number of pathological ways (p. 18, Validating drug-like binding of PPI inhibitors).
Since the prior art at the effective filing date of the present application did not provide guidance for a method of treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis comprising administering a compound that binds, associates or interacts with the TrxG-MLL complex and interferes with, prevents or inhibits binding between R2R1 and a member of the TrxG-MLL complex, it is incumbent upon the instant specification to do so. Finally, methods of “preventing” diseases and/or conditions are usually reserved for vaccines and/or infectious diseases, and no known compound has been identified that is able to prevent aberrant or defective ciliogenesis. There is no reason why one skilled in the art would expect a single compound to prevent all of the diverse aspects of the genus of claimed disease and conditions.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the claimed invention.
CONCLUSION
Since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex so as to interfere with, prevent or inhibit binding between R2R1, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to practice the claimed invention.
(Written Description)
Claims 1, 3, 6, 7, 9, 11, 13, and 14 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 encompass a genus of methods for treating and/or preventing diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that interferes with, prevents or inhibits binding between R2R1 with TrxG-MLL and/or a component or subunit thereof.
In regard to the genus of compounds encompassed by the claimed methods, Applicant’s compounds include nucleic acids, antisense oligos, carbohydrates, proteins, peptides, small molecules that interfere with the TrxG-MLL complex, and antibodies (including antigen binding or target binding fragments thereof) capable of interfering with, blocking or neutralizing binding of R2R1 to the TrxG-MLL complex p. 6, 1st para., p. 10, last para.to p. 12, 2nd para. of Applicant’s specification. However, Applicant’s disclosure has not demonstrated nor described a compound that treated a subject with any of the claimed diseases and/or conditions.
Dependent claims 3, 9, and 11 encompass a genus of compounds that bind to or associate with the R2R1 binding sites within the PRC1 and/or TrxG-MLL complex, which are further limited to compounds that interfere with, prevent or inhibit binding between R2R1 and the TrxG-MLL complex, which are further limited to R2R1 proteins and peptides, and neutralizing antibodies. However, Applicant’s disclosure has not demonstrated nor described the binding sites between R2R1 and the TrxG-MLL complex, nor any compound, peptide, or antibody that is capable of interfering with, preventing, or inhibiting the interaction.
Dependent claim 7 encompass a genus of compounds that bind, associate or interact with the TrxG-MLL complex, which are further limited to include nucleic acids, antisense oligonucleotides, carbohydrates, proteins, peptides, small molecules, and antibodies including antigen binding or target binding fragments thereof. However, Applicant’s disclosure has not demonstrated nor described any these compounds that bind, associate or interact with the TrxG-MLL complex, and are capable of achieving the claimed method.
Dependent claims 13 and 14 encompass a genus of diseases and/or conditions associated with aberrant or defective ciliogenesis to be treated and/or prevented, which are limited to ciliopathies such as COPD. However, Applicant’s disclosure has not demonstrated nor described a subject with any of the claimed ciliopathies that was treated by the claimed method.
Under the new Written Description Guidelines for antigen binding proteins molecules, the Examiner is directed to determine whether one skilled in the art would recognize that the applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination: on 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been re-evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for methods of treating and/or preventing a pulmonary and/or airways disease and/or condition caused with aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex, and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex. Additionally, no working examples were provided that utilize a cell culture system representative of a disease and/or condition associated with aberrant or defective ciliogenesis by administering to a compound that binds, associates, or interacts with the TrxG-MLL complex, and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex. Therefore, the specification does not provide sufficient description on how to practice the claimed method.
In regard to instant claims encompassing a genus of methods for treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex and interferes with, prevents, or inhibits binding between R2R1 and subunits of the TrxG-MLL complex, Applicant describes the TrxG-MLL complex as a multi-subunit protein complex comprising the core members TrxG and MLL, as well as associated members DPY-30 and ASH2L, which maintain active gene expression by histone H3 lysine K4 methylation. However, Applicant has not described a compound that binds, associates, or interacts with the TrxG, MLL, DPY-30 or ASH2L, that is capable of interfering with, preventing, or inhibiting binding between R2R1 thereby treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis complex.
By contrast, what Applicant’s has attempted to describe is a protein/protein interaction between R2R1 (alias FAM25C) and the DPY-30 and ASH2L members of the TrxG-MLL complex, and has attempted to extrapolate that because shRNA inhibition of the R2R1 gene in primary bronchial epithelial cells (PBEC) upreguates genes associated with ciliogenesis and/or cilary movement which are also involved with COPD (Figures 3-9, 13-18 of the disclosure), and appears to increase number of ciliated PBECs from both normal and COPD patients (Figures 22 and 23), this supports a method of treating and/or preventing diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis in a subject by administering any compound that binds, associates or interacts with the TrxG-MLL complex, or more specifically, a compound that interferes with, prevents, or inhibits binding between R2R1 with the TrxG-MLL complex.
In light of this limited description, Applicant’s claimed genus of methods suffer from a lack of written description on at least two grounds.
First, neither Applicant’s disclosure nor the prior art (see more below) describe that either TrxG, MLL, ASH2L, or DPY-30 can regulated ciliogenesis, much less be generically targeted by a genus of compounds that interfere with, prevent, or disrupt R2R1 binding in order to treat and/or prevent a pulmonary and/or airway disease or condition of ciliogenesis.
Second, neither Applicant’s disclosure nor the prior art (see more below) sufficiently describe the interaction between R2R1 and the TrxG-MLL complex that would allow one of ordinary skill to predictably make and use a compound which binds, associates or interacts with the TrxG-MLL complex so as to allow the treatment and/or prevention of a disease or condition of ciliogenesis. Specifically, Applicant has indicated that by a yeast two hybrid screen that R2R1 was capable of interacting with DPY-30 (1/7 hits, data not shown) (p. 21, 3rd para.). Applicant goes on to demonstrated that when HA-tagged R2R1 is mixed in vitro with members of the TrxG-MLL complex, the anti-HA R2R1 can co-immunprecipitate ASH2L and perhaps DPY-30 (Fig. 2, p. 22, 2nd para.).
However, Applicant has not described the functional effects of the putative R2R1 binding on TrxG-MLL activity, in order to establish that such an interaction would predictably affect methyltransferase activity and/or is responsible for the observed effects of R2R1 on aberrant or defective ciliogenesis.
Finally, Applicant has not provided sufficient description for the making and using a compound that binds to or associates with R2R1 binding sites within the TrxG-MLL complex such that it can achieve the claimed function.
DISCLOSURE OF STRUCTURE & RELEVANT IDENTIFYING CHARACTERISTICS
The Applicant has provided the following amino acid sequence listings of SEQ ID NO for R2R1 proteins.
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Specifically, Applicant describes SEQ ID NOs:5 and 6 as corresponding to mouse and human R2R1 proteins, respectively, and asserts that these proteins or peptide fragments thereof bind, interact or otherwise associate with a component of the TrxG-MLL complex (p. 9. 3rd & 4th para.). However, MPEP 2163 states that “A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence”. Importantly, neither the specification nor the art indicate a relationship between the structure of the claimed genus of compounds and the ability to bind, associates or interacts with the TrxG-MLL complex, so as to interfere with, prevent or inhibit binding between R2R1 with a subunit of the TrxG-MLL complex so as to allow the treatment and/or prevention of a disease or condition of ciliogenesis
Accordingly, if the skilled artisan sought to generate the claimed genus of compounds, they would first need to know which sequences in the R2R1 and/or TrxG-MLL complexes could be chosen to predictably produce a compound capable of the claimed function. Hence, based on the written description guidelines, the Examiner should conclude that the Applicant was not in possession of the claimed genus of compounds, and the present specification provides no guidance nor description to any rational in choosing the sequences that could achieve the claimed function. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the genus of compounds.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that methods for treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis by administering to a subject a compound that binds, associates, or interacts with the TrxG-MLL complex so as to interfere with, prevent or inhibit binding between R2R1 is not a highly successful technique or has highly variable results. Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in practicing the instant invention.
Although the TrxG-MLL complex comprising components such as ASH2L and DPY-30 was known in the prior art for controlling histone methylation, it was not known to be involved in conditions associated with aberrant or defective ciliogenesis. Specifically, the prior art of Veazy et al. (Alc Res:Current Reviews, 2013;35(1):77-85) reviews the role of the TrxG-MLL complex with respect to general histone modification and epigenetic regulation (see Fig. 3 below), and teaches MLL was originally identified as playing a role in the development of different types of leukemia, but admits “very little information exists on individual TrxG proteins or their biochemical functions” (p. 82, 1st para.)
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Veazy states that the complex is thought to promote cell-specific patterns of gene expression by regulating global and gene-specific H3K4 methylation during early embryonic development as evidenced from MLL mouse gene knockouts, and that the proper functioning of TrxG complexes is indispensable to converting bivalent loci into an actively transcribed state required for neurogenesis, yet “much remains unknown regarding the temporal and tissue-specific regulatory evens these protein promote” (p. 83, 1st & 2nd para.). Thus, the prior art does not predict or reasonably suggest a compound that binds, associates, or interacts with the TrxG-MLL complex that could predictably treat and/or prevent a disease and/or condition associated with aberrant or defective ciliogenesis
In regard to the interaction between R2R1 and members of the TrxG-MLL complex, the prior art is silent with respect to such an interaction. Furthermore, based on other known protein interactions with the TrxG-MLL complex, the in vitro binding data provided by Applicant’s Fig. 2 does not provide a sufficient description for making and using a compound that binds, associates or interacts with the TrxG-MLL complex, nor compounds that interfere with, prevent or inhibit the binding of R2R1 to achieve the claimed function effects. Specifically, the prior art of Ullius et al. (Nuc Acid Res, 2014, 42(11)6901-6020), see IDS filed 7/02/2021) demonstrated in vitro binding between MYC and ASH2L, but could not effect methyltransferase activity of the TrxG-MLL complex by deleting the in vitro interaction domain between ASH2L and MYC (p. 6906, col 2). Thus, the prior art indicates that making and using a compound that interferes with, prevents or inhibits binding between R2R1 and a member of the TrxG-MLL complex was not predictable and would have required undue experimentation.
Moreover, even with modern screening techniques, the generation of such compounds capable of the claimed function based on the limited disclosure by the Applicant was not predictable. Specifically, the prior art of Arkin et al. (Assay Guidance Manual, 2012, Eli Lilly & Co) teaches that is has been difficult to identify small molecules, antibodies or peptide inhibitors of protein-protein interactions (PPI). Often sited reasons for this challenge include a) the flat nature of PPI interfaces, which sometimes lack deep grooves where small molecules can stick, b) large contact area at the interface, which often exceeds the surface area of a drug-sized molecule, and c) bias in the screening libraries (p. 1, Introduction). Arkin goes on to state that even with modern screening formats, the screening for PPI inhibitors can identify compounds with many mechanisms of inhibition, some of which are undesired, such as direct assay interference, nonspecific binding, and covalent modification. Moreover, PPI screens must be optimized for the used of detergents, because no one detergent removes all aggregates, as well as for the sensitivity to diluting compounds such as DMSO, and necessitate multiple orthogonal assays because compounds will interfere with assays in multiple ways, some of which are difficult to predict (pgs. 2-3, General Considerations). Finally, Arkin discloses that although a primary screen may produce a set of compounds that might be active, many of these compounds will not be optimizable into a qualified drug that can be used in a subject. Moreover, the screens suffer from artifactual mechanisms that lead to activity in the primary assay, but do not translate into in vivo activity. A well-described and very common example is compound aggregation, which can interfere with protein structure in a number of pathological ways (p. 18, Validating drug-like binding of PPI inhibitors).
Moreover, methods of “preventing” diseases and/or conditions are usually reserved for vaccines and/or infectious diseases, and no known compound has been identified that is able to prevent aberrant or defective ciliogenesis. There is no reason why one skilled in the art would expect a single compound to prevent all of the diverse aspects of the genus of claimed disease and conditions.
Since the prior art at the effective filing date of the present application did not provide guidance for a method of treating and/or preventing a disease and/or condition of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis comprising administering a compound that binds, associates or interacts with the TrxG-MLL complex and interferes with, prevents or inhibits binding between R2R1 and a member of the TrxG-MLL complex, it is incumbent upon the instant specification to do so. Not knowing, absent further experimentation and screening, which compound predictably binds, associates or interacts with the TrxG-MLL complex or a compound that interferes with, prevents or inhibits binding between R2R1 and a member of the TrxG-MLL complex, leads to one having no predictability or expectation of success for the function of treating and/or preventing a disease and/or condition associated with aberrant or defective ciliogenesis. Such random experimentation to identify at a later time what structure or variant or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. Furthermore, functionally defined genus claims (i.e., a binds, associates, interacts with, interferes with, prevents or inhibits binding) can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
CONCLUSION
Therefore, the examiner concludes that there is insufficient written description of the instantly claimed genus of methods and compounds. Specifically, there is limited description of the structure-function relationship between the claimed genus of compounds and their ability to be used in a method to treat and/or prevent diseases and/or conditions of the pulmonary system and/or airways caused by aberrant or defective ciliogenesis, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the genus of compounds encompassed by the claimed methods.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 9/2/2025 are acknowledged.
Applicant argues that instant methods of treating and/or prevent pulmonary and/or airway diseases and/or conditions that are caused by aberrant or defective ciliogenesis, comprising administering a compound that interferes with, prevents, or inhibits binding between native or wild-type R2R1 with PrC1 and/or TrxG-MLL and/or a component or subunit of either, are enabled and sufficiently described.
Specifically, Applicant argues that they have established a role of R2R1 in the regulation of ciliogenesis, as evidenced by Example 1, 1.2 demonstrating the siRNA knock down of R2R1 upregulated ciliogenesis in cultured human pulmonary bronchial epithelium. Applicant argues that based on these siRNA findings, one of ordinary skill would have understood how to make and use an inhibitory antibody or some other compound which blocks R2R1 function in order to upregulate ciliogenesis. Applicant argues that the knock down data established the cellular role of R2R1, and that one of ordinary skill would have understood that any compound that achieves the same effect on R2R1 function would also achieve the same outcome without undue experimentation. Applicant cites MPEP 2107.01 (III), wherein courts have found utility for therapeutic inventions despite the fact that an inventor is at a very early stage in the development of a pharmaceutical product or therapeutic regimen based on a claimed pharmacological or bioactive compound or composition.
Furthermore, Applicant argues that the specification provides sufficient guidance to one of ordinary skill to prevent R2R1 from binding to, or interacting with PrC1 complex through the RNF2 subunit and a member of the TrxG/MLL complex such as DPY-30 and/or ASH2L, so as to upregulate ciliogenesis. Applicant argues that one of ordinary skill would have understood how to make and use a compound such as an inhibitory peptide, or R2R1 fragment, or small molecule interacting with R2R1 interface with RNF2 and/or the R2R1 interface with BPY-30/ASH2L in order to upregulate ciliogenesis.
Applicant's arguments have been fully considered but they are not persuasive.
First, in regard to Applicant’s arguments that the disclosure of knocking down R2R1 upregulating ciliogenesis sufficiently enables and describes the genus of compounds for disrupting the protein interactions of R2R1 is a clear scientific overreach. Although siRNA, anti-sense oligos, gene disruption all reduce R2R1 function, they do so in a very generic manner (loss of the protein). By contrast, Applicant is attempting to assign a total loss of protein function to particular protein interactions with the PrC1 and/or Trx-MLL complexes or subunits thereof with no evidence that these interactions affect ciliogenesis in any manner. Although the total generic loss of function encompasses these species of subfunctions, there is no manner to predict that the loss of subfunctions was necessary or sufficient to have equated to a total loss of function, and neither Applicant’s disclosure nor the prior art would have predicted that the loss of these particular protein interactions would have recapitulated the total loss of function. Besides, MPEP 2164.04 is clear that although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In reVickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In reCook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971), in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In reSoll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In reFisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In reWright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In reVaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because in art areas having a high degree of uncertainty (i.e. the unpredictable arts) it is not reasonably predictable from the disclosure of one species (e.g., siRNA), what other species will work (e.g., inhibitory peptide between R2R1 and PrC1).
Second, even if the scientific leap could have been predictably made between equating the function between R2R1 knock down and the disruption of the particular protein interactions of R2R1 with members of the PrC1 complex and/or TrxG MLL complex, no compounds for these particular functions are disclosed or sufficiently described by Applicant’s specification. Neither Applicant’s disclosure nor the prior art describe that either TrxG, MLL, ASH2L, or DPY-30 can regulated ciliogenesis, much less be targeted by a genus of compounds to treat and/or prevent a disease or condition of ciliogenesis by interfering with the interaction of R2R1. Furthermore, neither Applicant’s disclosure nor the prior art sufficiently describe the protein interaction between R2R1 and members of the PrC1 complex or TrxG-MLL complex that would allow one of ordinary skill to predictably make and use a compound which binds, associates or interacts with the PrC1 and/or TrxG-MLL complex so as to allow the treatment and/or prevention of a disease or condition of ciliogenesis.
Finally, in regard to Applicant’s arguments that the courts would have found utility in the claimed methods despite only the in vitro findings with R2R1 knock down, Applicant is reminded that In Crossv.Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985), although the Federal Circuit affirmed that a pharmacological utility had been disclosed in the application, it was based on finding that Iizuka’s application had sufficiently disclosed a pharmacological utility for the compounds and it distinguished the case from cases where only a generalized “nebulous” expression, such as “biological properties,” had been disclosed in a specification. Such statements, the court held, “convey little explicit indication regarding the utility of a compound.” Cross, 753 F.2d at 1048, 224 USPQ at 745 (citing In re Kirk, 376 F.2d 936, 941, 153 USPQ 48, 52 (CCPA 1967)). In instant case, Applicant has not demonstrated the pharmacological utility of any compound in vitro or in vivo capable of interfering with, preventing, or inhibiting binding between R2R1 with a subunit of the PrC1 complex and/or TrxG-MLL complex.
Withdrawn Claim Rejections - 35 USC § 112(b)
The prior rejection of Claims 3, 6, and 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite are withdrawn in light of Applicant’s amendments to provide proper antecedence.
Conclusion
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
No claims are allowed.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631