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 .
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 reference has by cited by the examiner on form PTO-892, they have not been considered.
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.
Claim 1, 3, 4, 5, 6, and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 3 are rejected as indefinite because they are drawn to “lung restricted antibodies” which seems to be used interchangeably in the specification with “lung restricted autoantibodies” but no statement of equivalence or distinction between the two has been made.
In the brief description of the drawings, it says “lung restricted antibodies (LRA)” (paragraph 22), but earlier in the specification it states “lung restricted autoantibodies (LRA)” (paragraph 44). It is unclear whether the applicant is attempting to delineate between these two phrases, making claim interpretation indefinite. For the purposes of examination, they will be interpreted to be the same thing. Examiner recommends amending the specification to use consistent language or providing an explicit statement of equivalence for better clarity.
Claims 4 and 5 are rejected as indefinite because the meaning of “anti-lung restricted antibodies” is unclear. There is no definition of an anti-lung restricted antibody in the specification. Conventional knowledge within the state of the art does not elucidate the intended definition of this term. Furthermore, how an anti- IL1β antibody could be a type of anti-lung restricted antibody, as recited in claim 5, is unclear since they would conceivably bind to different things, namely a chemokine and a lung restricted antibody, respectively. In addition, IL1β is present throughout the body, not just in the lung. Therefore, an anti-IL1β antibody could bind to and be present throughout the body as well; it is not an anti-lung restricted antibody. Since there is no apparent definition for the term “anti-lung restricted antibodies” it will be treated as the term anti- IL1β antibody for the purposes of examination.
Claim 6 is rejected as indefinite because it is a dependent claim which refers back to itself instead of depending from another claim. For the purposes of examination, claim 6 will be treated as being dependent from claim 1.
Claim 8 is rejected as indefinite because the metes and bounds of “derivatives thereof” is unclear. To what extent can the claimed complement inhibitors be changed and still be considered a derivative? Do derivatives require the same target or simply need to act on the same pathway?
Claim 10 is rejected as indefinite for failing to recite a meaningful final step that leads to achieving the method goal as indicated within the preamble. The preamble of this claim recites determining likelihood of primary graft dysfunction (PGD), but the body of the claim is only drawn towards detecting IL1β with no further direction on what to do with that information in order to determine PGD onset.
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, 2, 4, 5, and 6 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 claims are drawn to an anti-IL1β antibody but without a specific combination of six CDRs for the antibody. The claims are further drawn to Canakinumab and Anakinra, which are commercially available anti-IL1β antibodies, or derivatives thereof.
Claiming an antibody based on the fact that it binds to IL1β without specific CDR sequences is not sufficient to satisfy the written description requirement. The MPEP clearly states: “…disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional.” See MPEP 2163.
The hyper variable regions (HVRs), i.e. complementary 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 and envision the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (cited on form 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, such as Canakinumab and Anakinra, 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 (pg. 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. As a further example, see Chen (cited on from 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 disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Claim Rejections - 35 USC § 101
In Prometheus, the Court found that "[i]f a law of nature is not patentable, neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Additionally, "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law." Flook, 437 U. S., at 590; see also Bilski, 561 U. S., ("[T]he prohibition against patenting abstract ideas 'cannot be circumvented by'.., adding 'insignificant post-solution activity'" (quoting Diehr, supra, at 191-192)).
The Court also summarized their holding by stating "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
Thus, if the claim recites or involves a judicial exception, such as a law of nature/natural principle or natural phenomenon (e.g., the law of gravity, F=ma, sunlight, barometric pressure, etc.), and/or something that appears to be a natural product (e.g., a citrus fruit, uranium metal, nucleic acid, protein, etc.), then the claim only qualifies as eligible subject matter if the claim as a whole recites something significantly different than the judicial exception itself.
In the instant case, based upon an analysis with respect to the claim as a whole, claims 10-12 and 14 are determined to be directed to a judicial exception without significantly more. The rationale for this determination is explained below in view of controlling legal precedent set forth in 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 74618) dated December 16, 2014 and 2019 Revised Patent Subject Matter Eligibility Guidance (84 FR 50) dated January 07, 2019.
Step 1: Yes
The instant claims 10-12 and 14 are directed to a method of determining the likelihood of primary graft dysfunction, which is a process.
Next, Step 2, is the two-part analysis from Alice Corp. (also called the Mayo test) to determine whether the claim is directed to laws of nature, natural phenomena, and abstract ideas (the judicially recognized exceptions). (In Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014) the Supreme Court sets forth a two-step test for determining patent eligibility.
First, determine if the claims encompass a judicial exception (a natural phenomenon/law of nature/abstract idea) (Step 2A/1).
If so, then ask whether the remaining elements/steps, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to ‘“transform the nature of the claim’ into a patent-eligible application.” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297) (Step2A/2). Put another way, there must be a further “inventive concept” to take the claim into the realm of patent eligibility. Id. at 2355. In the recent Myriad v Ambry case, the CAFC found claims (drawn to methods comprising obtaining tissue samples, analyzing sequences of cDNA and comparing germline sequences of a gene to wild-type sequences) to encompass the abstract mental processes of ‘comparing’ and ‘analyzing’. Recitation of specific techniques (in Myriad claims 7 and 8 further recited hybridization and PCR) were deemed not “enough” to make the claims patent-eligible since the claims contained no otherwise new process. The elements/steps recited in addition to the judicial exception did nothing more than spell out what practitioners already knew).
Step 2A/1: Yes
The instant claims 10-12 and 14 encompass detecting IL1β in a subject to determine the likelihood of primary graft dysfunction in a subject. Since higher levels of IL1β is known in the art to be associated with higher instances of primary graft dysfunction in lung transplant patients, which is a process that is governed by a law of nature, these claims are directed toward a judicial exception. The chemokine IL1β is a naturally occurring factor that is expressed differently during pathology of primary graft dysfunction apart from any human action. The relation between the levels of expression of the IL1β and pathology of primary graft dysfunction exists in principle and is a consequence of the ways these factors are metabolized by the body, entirely natural process, a natural phenomenon, and thus a judicial exception.
Next, prong two of Step 2A requires identifying whether there are additional elements recited in the claim beyond the judicial exception(s) and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. “Integration in to a practical application” requires an additional element or combination of additional elements in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such as the claim is more than a drafting effort designed to monopolize the exception.
Step 2A/2: No
In the instant case, the claims do not recite any additional elements to integrate the judicial exception into a practical application because all the steps (i.e. detecting) of the claimed methods are limited to only those that detect naturally a occurring factor during a naturally occurring pathology. The instant situation is similar to the one in Mayo, wherein the claims recited method of administering drugs to a patient and measuring the levels of certain metabolites in the blood, wherein the level of metabolites indicates whether to adjust the dosage. The Supreme Court held that the claims recited a natural law and did not “include any “additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S., 132 S. Ct. 77, 101 USPQ2d 1961 (2012).
Step 2B: No
Finally, claims 10-12 and 14 do not recite any elements, or combinations of elements to ensure that the claim as a whole amounts to significantly more than the judicial exception because the active step of the claims—detecting a marker—represents a routine step that are recited at a high level of generality and encompass well-understood and purely conventional routine techniques in the art.
Thus, for reasons fully explained above, claims 10-12 and 14 do not satisfy the requirement of 35 U.S.C. 101 and are therefore rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 7-9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wiebke et al., Clinical and Translational Research, 2014 (hereafter Wiebke).
Claims 7-9 are drawn to a method of preventing or treating the incidence of primary graft dysfunction in a subject, comprising administering a complement inhibitor, wherein the complement inhibitor comprises Eculizumab, Cinryze, or Rocunest, or derivatives thereof, and administering plasmapheresis and/or a complement blockade.
Wiebke teaches administering a complement inhibitor, a C1 esterase inhibitor (C1-INH) like Cinryze, to patients demonstrating PGD (pg. 1185, Abstract Methods section). Wiebke further teaches administering plasmapheresis (pg.1188, right side, middle of page).
Therefore, the claimed invention is anticipated by Wiebke.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 5 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Akbarpour et al., The Journal of Heart and Lung Transplantation, 2019 (hereafter Akbarpour ) in view of Ghaidan et al., Nature Communications, 2022 (hereafter Ghaidan).
Claims 1, 2 and 13 are drawn toward a method for preventing or reducing the incidence of primary graft dysfunction of a subject, wherein the subject is a human being, comprising screening the subject for lung restricted antibodies and administering an anti-IL1β antibody and/or a complement inhibitor.
Akbarpour teaches that lung-restricted antibodies are a risk factor for PGD (Abstract, line 7) and explicitly teaches screening for them in human patients (pg.598, right side, last paragraph). Akbarpour also teaches that PGD could be treated by inhibiting IL1β with an anti- IL1β antibody (Figure 2) and provides motivation for pursuing this option as a therapeutic target because of its “potential for rapid clinical translation” (pg. 597, right side, Lines 6-9). Furthermore, Akbarpour teaches that complement inhibition, if successful, would “immediately impact clinical practice” because of commercially available FDA approved complement inhibitor drugs (pg. 598, left side, first paragraph).
While Akbarpour suggests treating PGD using an anti- IL1β antibody, it does not teach actually implementation of IL1β inhibition therapy.
Ghaidan teaches that the incidence of primary graft dysfunction can be reduced by using IL1β adsorption, which captures the chemokine using a porous material, thereby mitigating its downstream effect (Figure 1 and Figure 5). Thus, Ghaidan demonstrates that blocking IL1β is an effective therapeutic route for PGD (pg. 1, Abstract).
It would have been obvious to one of skill in the art to combine Akbarpour and Ghaidan.
Ghaidan demonstrates that blocking IL1β successfully reduced PDG, so one would be motivated to seek therapeutic treatments that targeted IL1β. The chemokine adsorber in Ghaiden and the anti-IL1β antibody in the instant application both serve to mitigate the consequences of IL1β that promote PGD, albeit in mechanistically different ways. Given that commercially available anti-IL1β antibodies, such as Canakinumab, were already available for use in humans, and the motivation from the applicant's own work in Akbarpour to pursue an anti-IL1β treatment because of its translatability, in addition to the proof of concept from Ghaidan’s results, it would have been obvious to one of skill in the art to pursue treatment of PDG with an anti-IL1β antibody.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Akbarpour and Ghaidan, as applied to claims 1-2, and 13 above, and in further view of Crespo et al., Frontiers, 2021 (hereafter Crespo).
Claim 3 is drawn towards a screening step, wherein the screening comprises an autoantibody multiplex assay.
Akbarpour and Ghaidan not teach that the antibody screen is achieved with an autoantibody multiplex assay.
Crespo teaches the use of a LABScreen multiplex assay to screen subjects prior to kidney transplant for problematic antibodies that may contribute to antibody-mediated rejection (pg. 2, first paragraph). This is the same brand of assay suggested in the instant application. Therefore, Crespo teaches that the desired kit in claim five was already commercially available.
It would have been obvious to incorporate the teachings of Crespo into those of Akbarpour and Ghaidan since it was a readily and commercially available method of achieving the antibody screening that Akbarpour teaches in the field of organ transplant.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Akbarpour and Ghaidan, as applied to claims 1-2, and 13 above, and in further view of Church et al. Current Opinion in Molecular Therapeutics, 2000 (hereafter Church).
Claim 6 is drawn towards an anti-IL1β antibody, comprising Canakinumab or Anakinra or derivatives thereof.
Akbarpour and Ghaidan do not teach an anti-IL1β antibody comprising Canakinumab or Anakinra or derivatives thereof.
Church teaches that Canakinumab was a known anti-IL1β antibody that could be using in humans for treatment of disorders.
It would have been obvious to incorporate the teachings of Church into the teachings Akbarpour and Ghaidan since it was a readily and commercially available anti-IL1β antibody, which Akbarpour suggests as potential treatment option for PGD and Ghaidan further provides supporting proof of concept as a successful therapeutic pathway. Furthermore, it was FDA approved for use in humans.
Claims 10-12 and 14 is/are is rejected under 35 U.S.C. 103 as being unpatentable over Ghaidan in view of Church.
Claims 10-12 and 14 are drawn to determining the likelihood of primary graft dysfunction in a subject comprising detecting the presence of IL1β in a sample following lung transplantation, wherein the sample can be, among other things, mucous, wherein the sample is taken from the interstitial space of the lungs, wherein the subject is a human being.
Ghaidan teaches detection of IL1β before, during, and after lung transplantation using a bronchoalveolar lavage, which would retrieve lung mucous from the interstitial space (Figure 3, and 4).
Ghaidan does not teach that the subject is a human being.
Church teaches that IL1β can be detected in human beings (pg. 3, left side, last paragraph).
It would be obvious to combine the teachings of Ghaidan and Church to detect the presence of IL1β in humans undergoing lung transplantation in order to implement therapeutic benefits for humans.
Conclusion
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675