DETAILED 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 .
Election/Restrictions
2. Applicant’s election with traverse of the following election of an anemia: anemia caused by one or more mutations and/or deletions on human chromosome 5 or in an ortholog thereof. Examiner agrees with applicant in regards to claims 2 and 3 not being a type of anemia. Applicant elects erythropoietin as the species for secondary therapeutic agents recited in claim 6, 7, 13 and 14. The reply filed on 5/19/2026 is acknowledged.
3. The election with traverse filed 5/19/2026 is acknowledged. Claims 1-14 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 06/26/2023, 10/11/2024, and 3/18/2025 and the references cited therein have been considered, unless indicated otherwise.
Specification
5. The use of the terms such as MethoCult (page 118) and NextSeq (page 111), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please review the specification for other Trademarks and correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claim 3 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “sufficient” in claims 3 and 10 is a relative term which renders the claim indefinite. The term “sufficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
7. Although the term “insufficiency of serine/threonine-protein kinase RIOK2” in claim 4 is towards a non-elected species, it is worth noting that the term is a relative term which renders the claim indefinite. The term “insufficiency of serine/threonine-protein kinase RIOK2” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear whether what is insufficient about the protein kinase.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
8. Claim 2-3 and 9-10 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2-3 and 9-10 recite “wherein the defective erythropoiesis is characterized by increased apoptosis in erythroid progenitors” and “wherein the defective erythropoiesis is characterized by an inability to produce sufficient red blood cells in bone marrow”; however, these limitations do not in any way further limit the methods of treatment of claims 1 and 8, respectively from which claims 2-3 and 8-10 are depend, respectively; i.e., such a limitation does not alter or relate to the antibody (anti-IL-22 antibody and anti-IL-22RA1 antibody), method step or patient population of the methods of treatment in the independent claims. Therefore, claims 2-3 and 9-10 fail to further limit the subject matter of the claim upon which they depend on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Written Description
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.
The following rejection is a written description rejection. This written description rejection has two issues. One issue regarding written description is lack of antibody structure and the other issue is regarding the broadly claimed genus of mutations and deletions of human chromosome 5.
9. First, claims 1-14 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 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-14 are drawn to a method of a method of treating an anemia caused by defective erythropoiesis and promoting differentiation of an erythroid progenitor cell toward a mature red blood cell in a human subject in need thereof, the method comprising administering to the human subject an effective amount of an anti-IL-22 antibody or an antigen binding fragment thereof or an anti-IL-22RA1 antibody or an antigen binding fragment thereof.
The instant specification has provided the following antibody species: anti- IL-22 antibody or antigen-binding fragment thereof comprises IL22JOPTM monoclonal antibody, such as fezakinumab (page 2), antibody from Novus Biologicals targeting the extracellular domain of IL-22RA1 (page 19), recombinant antibodies such as single-chain antibodies, murine, chimeric, humanized, and human antibodies and multi-specific antibodies, as well as fragments and derivatives of all of the foregoing, which fragments and derivatives have at least an antigenic binding site (page 31), anti-IL-22 neutralizing antibody is available from Thermo Fisher Scientific (Cat# 16-7222-85) (page 58), Monoclonal anti-IL-22 (Clone IL22JOP) (page 92), and anti-IL-22 antibody (clone F0025) (page 127).
However, the claims encompass far more than the species disclosed in the specification. As noted above, the claims encompass a vast genus of antibodies described solely in terms of their function and/or a partial structure. The specification does not provide adequate written description to identify the broad genus of the claims because the specification does not disclose a correlation between the necessary structure of the antibody, and the claimed functions to be maintained (i.e. method of treating anemia). Thus, the specification does not distinguish the claimed genus from others, except by function. Although the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by members of the genus because, while the description of an ability of a claimed antibody may generically describe that molecule’s function, it does not describe the molecule itself. A definition by function does not suffice to define the genus because it is only an indication of what the antibody 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 antibodies, is highly variable (i.e. each different antibody capable of binding to Il-22 or IL-22RA1 would necessarily have a unique sequence of amino acids; see MPEP 2434), the functional characteristic of binding to something specific, is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies and variants thereof claimed only by a functional characteristic(s) and/or partial structure.
Additionally, the specification fails to disclose a representative number of species. As noted above, some claim embodiments do not recite any structure and other embodiments state that the antibody comprises three CDR sequences or a single light chain variable region, or heavy chain variable region. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. Although the specification discloses exemplary species, these species are not representative of the genus. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Furthermore, there is no description of an antibody comprising fewer than all six CDRs or variant having a particular sequence identity to the given heavy chain and light chain CDR sequences that have the recited functions, and thus, the specification does not describe species that reflect the variation within the genus.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g. see In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]; emphasis added. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claims, claimed only by a partial structure and functional characteristics and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous antibodies had not yet been identified and thus the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of antibodies claimed only by a partial structure and functional characteristics.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims 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.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of anti-Il-22 and anti-IL-22RA1 antibodies by the function of binds IL-22 and IL-22RA1, and/or a partial structure. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed antibodies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733). MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4).
Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28) additionally teaches that, “ ... Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6). Thus, the state of the art recognized that it is highly unpredictable that an antibody comprising one or even all six CDRs, wherein the CDRs are not in their proper order or in the context of framework sequences which maintain their required conformation would have the requisite antigen binding function. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the antibody per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a plurality of antibodies defined solely in terms of their function and/or comprising fewer than six CDRs that may not have the biological functions recited in the claims. Based on the teachings of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of antibodies.
Consequently, the vast genus of antibodies encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
Second, claims 1, 3, 8 and 11 is 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. Please note that claims 1 and 8 are rejected in this rejection because they are claims that claims 3 and 11 depend on. The issue is specifically regarding the “mutations and deletions” language. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure
that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claim is drawn to the method according to claim 1 and 8, a method of treating an anemia caused by defective erythropoiesis in a human subject in need thereof and a method of promoting differentiation of an erythroid progenitor cell toward a mature red blood cell wherein the subject is afflicted with an anemia caused by defective erythropoiesis, the method comprising administering to the human subject an effective amount of an anti-IL-22 antibody or an antigen binding fragment thereof or an anti-IL-22RA1 antibody or an antigen binding fragment thereof. Wherein the anemia caused by defective erythropoiesis is an anemia caused by one or more mutations and/or deletions on human chromosome 5 or in an ortholog thereof.
The specification teaches that subjects have an MDS and/or an anemia defined according to a genetic mutation, such as a del(5q)-mediated MDS (page 13), the mutation can include deletions in the q33.1, q33.2, q33.3 regions of human chromosome 5 (page 51), and the mutation can include a deletion in q15 region of human chromosome 5 (page 18).
The issue with regard to the written description provision is that the genus of one or more mutation and/or deletions on human chromosome 5 or in an ortholog thereof is not adequately described. The claims broadly encompass human chromosome 5 mutations and deletions. The specification provides no guidance regarding which nucleic acid or amino acid can be modified in the mutants, while maintaining any given function. Therefore, these structures (i.e., different forms) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the claimed defective erythropoiesis, and the claimed functions, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed mutations and/or deletions of human chromosome 5. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only one species has been described and this is not considered to be representative of the breadth of the genus. Therefore, given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed mutations or deletions of human chromosome 5, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565,1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in surviving results in the conversion of surviving’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the proteins per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
10. Claims 1-4, 6-11 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Schneider, et al. (Schneider, R., Schenone, M., Ferreira, M. et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med 22, 288–297 (2016). https://doi.org/10.1038/nm.4047), Ebert, et al. (Ebert, B., Pretz, J., Bosco, J. et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451, 335–339 (2008). https://doi.org/10.1038/nature06494), Shao, et al. (Shao Ll, Zhang L, Hou Y, Yu S, Liu Xg, et al. (2012) Th22 Cells as Well as Th17 Cells Expand Differentially in Patients with Early-Stage and Late-Stage Myelodysplastic Syndrome. PLOS ONE 7(12): e51339. https://doi.org/10.1371/journal.pone.0051339), in view of Kindsvogel, et al. (U.S Patent 8,287,866 B2, issued 10/16/2012) , and Xu, et al. (U.S. Patent 7,265,211 B2, issued on September 4, 2007),
Instant claim 1 recites a method of treating an anemia caused by defective erythropoiesis in a human subject in need thereof, the method comprising administering to the human subject an effective amount of an anti-IL-22 antibody or an antigen binding fragment thereof or an anti-IL-22RA1 antibody or an antigen binding fragment thereof.
Schneider, et al. teach the del(5q)/Rps14-haploinsuffiecient anemia proceeds through a p53-dpenedent block to erythroid differentiation characterized by apoptosis at the polychromatic to orthochromatic transition (abstract).
Ebert, et al. teach that reduced RPS14 expression produces increase erythroid apoptosis (paragraph 4). The limitation of instant claim 2 is not an added method step but a property of the anemia, taught by Ebert, et al. Ebert, et al. and Schneider, et al. teach the same defect manifests as impaired erythroid differentiation and reduced red blood cell output from the marrow, producing progressive anemia (paragraph 8 of Ebert and paragraph 11 of Schneider). The limitation of instant claim 3 is a characterization of the prior-art anemia (Ebert and Schneider). Ebert, et al. teach that the anemia of the del(5q) subtype of myelodysplastic syndrome is caused by deletion of chromosome 5 material (haploinsufficiency of RPS14 at 5q33), and Schneider, et a. teaches a murine RPS14-haploinsufficient model recapitulating the chromosome-5-deletion anemia through p53-dependent erythroid apoptosis.
Shao, et al. teach that IL-22 producing TH22 cells are expanded in patient with myelodysplastic syndrome.
Schneider, Ebert and Shao teach the anemia caused by defective erythropoiesis characters by increased apoptosis in erythroid progenitor, an inability to produce sufficient red blood cells in bone marrow, and an anemia caused by one or more mutations and/or deletion on human chromosome 5 or in an ortholog thereof. Schneider, Ebert and Shao do not teach the method of treating the species of anemia with anti-IL-22 antibody or anti-IL-22RA1 antibody.
However, Kindsvogel, et al. teach methods of antagonizing IL-22 (IL-TIF) by administering neutralizing antibodies directed to its receptor IL-22RA/zcytor11, and teaches that IL-22 decreases red blood cells and that Il-22 could play a role in a role in anemia. Kindsvogel, et al. further teach antibodies could be used as a therapeutic reagents in such diseases, therefore teaching treatment of anemia by administering an anti-IL-22RA1 antibody (paragraph 79, 80, 105, 106, claim 1 and 2). Xu et al teaches an anti-IL-TIF antibody zcytor16 that inhibits IL-TIF signaling which can benefit diseases of anemia (paragraph 434, "anti-IL-TIF antibodies, and its receptors, such as zcytor16 and soluble zcytor11/CRF2-4, are suitable reagents/targets for the diagnosis and treatment in variety of disorders, such as anemia").
It would have been obvious to one of ordinary skill before the effective filing date to administer the anti-IL-22 antibody of Xu, et al. and the antibody to receptor IL-22RA/zcytor11 of Kindsvogel, et al. to the patient population of Schneider, Ebert and Shao (human subject afflicted with the chromosome 5 deletion anemia of defective erythropoiesis) in order to treat anemia. Shao clearly states that IL-22 is elevated in myelodysplastic syndromes. Applying the treatment of Kindsvogel that antagonizing IL-22 reverses IL-22’s suppressive effective on red blood cells and treats anemia (paragraph 79). One of ordinary skill in the art would have had reasonable expectation of success, because Schneider teaches the erythroid apoptosis defect in this population is driven by innate immune signaling and Kindsvogel teaches that blocking the proinflammatory cytokine IL-22 relieves its suppressing of red blood cell production. The person of ordinary skill in the art would have been motivated to do so for disease treatment (anemia), and reasonably would have expected success because Xu teaches that data strongly support the involvement of IL-22 in hematopoiesis, and IL-22 decreases red blood cells, supporting the notion that IL-22 could play a role in anemia, and antagonists such as anti-IL-22 antibodies, IL-22RA soluble receptors, and anti-IL-22RA antibodies are suitable treatment; Shao teaches IL-22 producing TH22 cells are expanded in patient with myelodysplastic syndrome. Applying the known anti-IL-22 antagonist to an known disease such as anemia of defective erythropoiesis in which IL-22 is elevated is the use of a known technique to achieve a predictable result. Applying a known technique to a known method ready for improvement to yield predictable results is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.) Thus, the limitations of claims 1-4 are obvious over the above references.
Regarding instant claim 8, Xu, et al. teaches a method of promoting differentiation of an erythroid progenitor cell toward a mature red blood cell in a human subject in need thereof by administering the anti-IL-22 antibody (page 40, column 73, line 11-27, "IL-TIF may affect myeloid stem cells. Myeloid stem cells are daughter cells of the universal blood stem cells. They are progenitors of erythrocytes, monocytes (or migrated macrophages), neutrophil, basophil, and eosinophils. […] Thus, the results demonstrated that IL-TIF has an inhibitory activity on the proliferation and/or growth of a promyelocytic tumor cell line. Thus IL-TIF could play a role in anemia, infection, inflammation, and/or immune diseases. In addition, an antagonist against IL-TIF, such as antibodies or a soluble receptor, antagonist, could be used to block IL-TIF's activity on myeloid stem cells, or as therapeutic reagents in diseases such as anemia, infection, inflammation, and/or immune diseases"). The patient population has been taught above through Schneider, Ebert and Shao.
Instant claims 9, 10, and 11 are rejected for the same reasons above with the combination of references of Kindsvogel, et al., Ebert, et al., Schneider, et al. and Shao, et al.
Regarding instant claims 6, 7, 13 and 14, Xu et al teaches that the IL-TIF can be administered in combination with other cytokines such as erythropoietin (page 27, column 48, line 62-64).
11. Claims 5 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Ebert, et al., Schneider, et al., Shao, et al., Kindsvogel, et al., and Xu, et al. as applied to claims 1-4, 6-11 and 13-14, and in further view of NC-IUPHAR (Fezakinumab: Ligand page: IUPHAR/BPS guide to pharmacology. fezakinumab | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY. (2019, September 17). https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=9281)
Instant claims 5 and 12 are the method of claim 1, wherein the anti-IL-22 antibody or an antigen binding fragment thereof or an anti-IL-22RA1 antibody or an antigen binding fragment thereof is fezakinumab.
The teachings of Ebert, et al., Schneider, et al., Shao, et al., Kindsvogel, et al., and Xu, et al. are above.
Ebert, et al., Schneider, et al., Shao, et al., Kindsvogel, et al., and Xu, et al do not teach the IL-22 antibody is fezakinumab.
However, NC-IUPHAR teach Fezakinumab shows cross-species reactivity, blocking IL-22 receptor activation and cellular proliferation induced by murine, monkey and rat IL-22 in addition to the human cytokine. One of ordinary skill in the art could reasonably substitute the anti-IL-22 antibody or the anti-IL22RA1 antibody taught by Kindsvogel and Xu, for the anti-IL-22 antibody fezakinumab taught by NC-IUPHAR, to treat the patient population of Ebert, Schneider and Shao with reasonably success since fezakinumab antagonizes IL-22 the same as antibodies taught by Kindsvogel and Xu. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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