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 .
Claims 1, 8-15,17-20 are under consideration in the instant Office Action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See page 28. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code, like www. See MPEP § 608.01.
Claim Objections
Claims 1, 8-10 are objected to because of the following informalities: “iRhom2” is an acronym which stands for “Inactive Rhomboid family member 2” ; “ADAM17” is an acronym which stands for “ADAM metallopeptidase domain 17”; “TACE” is an acronym which stands for “tumor necrosis factor-a-converting enzyme”; “HB-EGF” is an acronym which stands for “Heparin-binding EGF-like growth factor” and needs to be spelled out in the claims, at least once in the first occurrence. Appropriate correction is required.
Further, claims 1 and 10 have bullet points to indicate indentations. These are not appropriate and need to be removed. The indentation of the phrase itself is sufficient to indicate a list of things. Applicant's attention is directed to MPEP 608.01(m) that deals with claim format. In particular, MPEP 608.01(m) discloses that each claim begins with a capital letter and ends with a period. In addition, it is disclosed that periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995). Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-20 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 “therapeutically sufficient dose” in claim 19 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. The common meaning for sufficient is enough or adequate. The common terminology used with therapeutic dosages is “therapeutically effective dose” to indicate that treatment is providing an active response the patient populations. The term “sufficient” in this vernacular is vague and indefinite since it is unclear what would be sufficient or enough.
Claim 20 calls for a product that falls under a “ a therapeutic kit of parts…”. It is unclear what is meant by “kit of parts…”.
Claim Rejections - 35 USC § 112
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, 8-15,17-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 8-15, 17-20 are directed to an antibody product that encompasses an antibody derivative and a method for treating or preventing an inflammatory condition in a subject by administering any of the antibody derivatives that specifically bind within a region of Loop 1 of human iRhom2. As such, the claimed antibody encompasses derivative antibodies defined by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. 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.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (region of Loop 1 of human iRhom2) and envisage the combination of six CDRs that will bind that antigen while encompassing derivative antibodies and fragments. First, even highly related CDRs may not bind the same target. See for example Kussie (in instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. The instant sequences in claim 1 meet this requirement but the antibody derivative language produces the written description issue. As a further example, see Chen et al., 1995 (in instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
The instant specification and instant claims disclose 6 pairs of heavy and light chains and CDRs starting at page 83 of the instant specification. However, as discussed above, without any way to determine how broad the genus of such derived antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all derived antibodies which possess the required functions required to treat or prevent any inflammatory disease nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Instant claim 1 recites heavy and light chain CDRS and VH and VL sequences. In addition to the claim not being self-containing, there is no limitation or exclusion in the claim language that prevents the modifications from occurring within the CDR region due to the claim language of “antibody derivatives”, which widens the scope of the claim to encompass an immense number of unknown molecules that share some identity to the claimed sequence and can bind to the claimed antigen. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
With respect to products in method claim 19, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new antibody, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “region of Loop 1 of human iRhom2” antibodies. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent 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. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds to a region of Loop 1 of human iRhom2, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of human iRhom2 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (in instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of derivative antibodies that binds to human iRhom2. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions 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.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible derivative antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states 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 they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific CDR sequences and heavy and light chain variable sequence pairs, the skilled artisan cannot envision the detailed chemical structure of all of the potential encompassed combination of antibodies, and therefore conception is not achieved until reduction to practice has occurred, 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 of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Removing the derivative language from claims 1 and 12 and limiting the antibodies and antigen binding fragments to the disclosed heavy and light chain CDRS and VH and VL sequences would overcome this specific written description rejection.
Therefore, claims 1, 8-15, 17-20 do not meet the written description requirement.
Claim Rejections - 35 USC § 112
Claim 19 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 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 make and/or use the invention. Claim 19 does not reasonably provide enablement for method for treating or preventing an inflammatory condition in a subject, the method comprising administering to the subject any derivative antibody or fragment thereof specifically binding within a region of Loop 1 of human iRhom2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature 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. In re Wands, 8 USPQ2d, 1400 (CAFC 1988).
The instant claim call for a method of treating an any inflammatory condition in a patient using any derivative antibody that specifically binding within a region of Loop 1 of human iRhom2 that requires no specific structure and claim 1 describe the antibody or call for undisclosed modifications to the disclosed structure does not alleviate the burden on unpredictability on how to perform this method successfully to the full conclusion of prevention. The dependent claims call for undisclosed modifications or differentiations in any of the VH and VL and CDRs of the claimed antibody. The patient population is never narrowed in the instant claim 19 except the subject includes human or animal. The instant claim is broad and generic while what is enabled is narrow and specific. The instant specification only provides examples of reducing effects of inflammation such as TNFa-shedding but fails to show any prevention of these effects in in vitro culture assays or even in a subject (see Example 15, pages 75-82 of instant specification). This treatment is targeted towards someone with an inflammatory condition which is a very broad subject pool. While the treatment with specifically disclosed antibodies shows positive results in cell cultures, it still fails to prevent these types of inflammatory conditions and the diseases it encompasses from occurring and therefore does not provide evidence that any inflammatory condition, is prevented or treated with non-specific antibodies. The instant specification does not provide any examples or evidence that this type of treatment would provide a benefit with unknown and undisclosed antibodies. Further, the instant specification fails to teach any other possible antibodies that have the instantly claimed function and able prevent any inflammatory disease in a patient population. There is no support provided in the instant specification or in the prior or instant art that teaches or supports the ability prevent any inflammatory disease.
The term “preventing” is generally understood in the art to encompass a total protection form disease or injury. Thus, given the high level of required effect, a high level of evidence showing prevention is also required. As noted above, however, there are no working examples in the instant specification demonstrating any therapy using the claimed antibody, nor any examples directed to the palliative, preventative, or curative treatment of any inflammatory disease. Therefore, the instant specification does not provide evidence or substantial guidance commensurate in scope with the broadly claimed method in how to use the method to prevent of any inflammatory disease.
Both at the time of filing and now, effective therapy for the prevention of any inflammatory disease have eluded researchers. The instant specification itself does not teach any method of prevention of any inflammatory disease. The prior art by Issuree et al., US 2015/0241429 (IDS, 5/29/2025), teaches treating inflammatory diseases such as Rheumatoid arthritis with anti-human iRhom2 antibodies but does not support the scope of preventing any inflammatory disease including RA. Thus, the relevant art recognizes the unpredictability of methods directed to preventing any inflammatory disease. The disclosure is not considered fully enabling for the claimed invention of prevention, since the state of the art teaches that prevention of any inflammatory disease with any agent is not currently possible.
Claim 19 encompasses an antibody with unknown modifications to prevent any inflammatory disease. The nature of the invention is clinical medicine comprising physiological modulation with an antibody for a medical disorder of the immune system, and is therefore of the highest complexity due to the complex nature of the immune system. The art does not provide compensatory teachings. The art teaches a limited amount of possible treatments to produce the limited result of effecting inflammation but does not teach the prevention of these types of diseases or any other immunological disease. Therefore, the prior art does not compensate for the failing of the instant specification. This speaks to the fact that while the art has observed possible antibodies that match the functional criteria of instant claim 1 that they have not yet identified all of the possible antibodies that read on the instant claims. There is still a lot of unknown in the art of what are all the possible antibodies that are functionally capable of meeting the functional imitations of the instant claims and would still require undue experimentation to determine what these antibodies are to prevent any inflammatory disease. One of ordinary skill would also have to take into account what type of immunological/ inflammatory disease this antibody is being administered to, to be able to determine if the antibody meets the required function of the instantly claimed antibody and prevent these diseases. This would require undue experimentation. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, the changes which can be made and still maintain activity/utility is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986).
As set forth above, inadequate guidance is presented in the specification to overcome the obstacles in practicing the claimed invention in its full scope. The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Given the tremendous breath of scope involving the instant claims, it would require undue experimentation for one of skill in the art to practice the claimed invention in its full scope. Therefore, the specification fails to provide enough guidance for one skilled in the art on how to practice the full scope of the instantly claimed method, thereby requiring trial and error experimentation to identify compounds meeting the functional limitations of the claims. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed. One of skill in the art would neither expect nor predict the appropriate methods of treating all inflammatory conditions in the manner claimed. Therefore, in view of the lack of guidance in the specification and in view of the discussion above, undue experimentation would indeed be required to make and use the invention commensurate with the scope of the claims.
The scope of the claims must bear a reasonable correlation with the scope of enablement. In re Fisher, 166 USPQ 18(CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
Undue experimentation would be required to produce the invention commensurate with the breadth of the claims based on the disclosure of the instant specification and the knowledge in the art. Reasonable correlation must exist between the scope of the claims and scope of enablement set forth. In view of the quantity of experimentation necessary, the limited working examples, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breadth of the claims, it would take undue trial and error to practice full scope of the claimed invention.
In conclusion, the instant claims encompass an invention of tremendous breadth, and essentially call for trial and error by the skilled artisan to begin discovering how to make the claimed invention without assisting the skilled artisan in such an endeavor, which amounts to undue experimentation and is therefore insufficient to constitute adequate enablement.
Conclusion
No claims are allowed.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675