DETAILED ACTION
Claims 1-22 are pending.
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.
Claim Objections
Claims 1, 12, 16, and 20 are objected to because of the following informalities: the acronym HNE is not defined. The first time an acronym appears in a claim set the acronym needs to be defined.
Appropriate correction is required.
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 1-22 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 1-22 recite the use of a monoclonal antibody. However, the specific antibody being used is not described in the claims or the instant specification. The claims are inclusive to a genus of monoclonal antibodies which possess the unique capabilities of specifically recognizing and binding to an HNE-generated neo-epitope consisting of an N-terminus or C-terminus.
In summary, the claims require a genus of monoclonal antibody products having (1) the ability to specifically recognize and bind to an HNE-generated neo-epitope consisting of an N-terminus or C-terminus, (2) binding to an N-terminus or C-terminus selected form one of the following HNE-generated fragments of calprotectin: SEQ ID Nos 1-7, (3) does not specifically recognize or bind to N-extended elongated version of said N-terminus amino acid sequence or an N-truncated shortened version of said N-terminus amino acid sequence, and (4) is raised against a synthetic peptide comprising said N-terminus or C-terminus. However, the claims recite minimal structural features or partial structural features.
MPEP § 2163 states that the written description requirement for a claimed genus may be
satisfied through establishment of a structure-function correlation (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) or through a sufficient
description of a representative number of species. Either is considered sufficient to show the
applicant was in possession of the claimed genus.
Regarding structure-function correlation, it is noted that one of skill in the art was aware
that there is a lack of structure-function correlation in antibody molecules. Evidence of such in
the form of publications in the art include the following.
First, the prior art recognizes that the full six CDR sequences are required to form the
part of an antibody, i.e., the paratope, that specifically binds the target antigen. See Al
Qaraghuli et al. (2020, Nature Scientific Reports 10:13969), who state that the six CDRs form a
continuous surface to form the paratope that binds the epitope of the cognate antigen.
However, the prior art also recognizes that a single protein can be bound by a very large
and structurally diverse genus of antibodies (i.e., there is no common structural relationship
even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For
example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to
a single protein can be generated, all with different sequences, and representative of almost
the entire extensive heavy and light chain germline repertoire (42/49 functional heavy
chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with
extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline
segment recombination) as well.
Lloyd et al. (2009, Protein Engineering, Eng. Design & Selection 22(3): 159-168) teach
that a large majority of VH/VL germline gene segments are used in the antibody response to an
antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced,
all but one of the 49 functional VH gene segments was observed, and that there are on average
about 120 different antibodies generated per antigen. Said reference also teaches that a wide
variety of VH and VL pairings further increase diversity. (See entire reference.)
Goel et al. (2004, J. Immunol. 173: 7358-7367) teach that three mAbs that bind to the
same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent
germline origin. Said reference further teaches that two of these mAbs recognize the same set
of amino acid residues defining the epitope (alternate amino acid residues spread over
the entire sequence), however, the relative contribution of each set of residues in the peptide
showed significant variation. The reference notes that all of the mAbs do not show any kind of V
gene restriction among themselves, implying variable paratope structure, despite that two of
these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (2014, J. Immunol. 192: 5398-5405) teach that two structurally diverse
germline mAbs recognizing overlapping epitopes of the same short peptide do so in different
topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches
that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell
response is composed of BCRs having a high degree of structural adaptability. Said reference
also teaches that the common epitope(s) also adopt distinct conformations when bound to
different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said
reference further teaches “It has been shown that both the framework region and the CDRs
have a considerable amount of inherent conformational plasticity...Therefore, it is not
surprising that distinct germline Abs recognize the same epitope by rearranging the
CDR conformations. This may well have implications of Ag specificity beyond the naive
BCR repertoire, because Kaji et al... have shown in a recent report that the B cell memory can
contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (2017, Biotechn. Bioeng. 114(6): 1331 -1342) teach substantial diversity
in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody
sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same
peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues
from different regions of the sequence and are discontinuous...de novo antibody designs
against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (2018, Biochemical Engineering Journal 137:365-374) teach what effects
mutations can have on an antibody's stability, solubility, binding affinity and binding specificity.
Rabia et al. report that an increase in antibody affinity can be associated with a decrease in
stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity
are not necessarily correlated and that and increase in affinity does not indicate an increase in
specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
Conversely, evidence also shows that some functionally diverse antibodies can share
some structural similarities, including an entire CDR region. See Igawa et al. (US 9,334,331 B2),
who disclose antibody Q153 that binds human Factor IXa. Q153 comprises a VH-CDR1
identical to the VH-CDR1 of antibody 11E12 disclosed by Gonzales et al. (US 10,421,807
B2). However, 11E12 specifically binds canine IL-31, a protein having no structural or functional
similarity to human Factor IXa. This illustrates that even when some CDR regions share 100%
structural identity, the antibodies in which they are comprised can have completely different
functions (i.e., binding specificities).
The combination of evidentiary publications thus underscores a lack of structure-function
correlation in antibody molecules.
Regarding a representative number of species, the instant specification fails to describe
a representative number of species to provide adequate written description of the claimed
genus as per MPEP § 2163. The instant specification fails to provide a description of the structural makeup of the antibody or a structure-function correlation with the antibody molecules. The specification also does not disclose the genus as broadly encompassed by the claims.
Applicant’s attention is directed to the recent decision in Amgen Inc. v. Sanofi, 872 F.3d
1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by
describing a newly characterized antigen. Specifically, the court referred to the decision in
Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the
patentee claimed a genus of antibodies containing a human variable region that has particularly
desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite
the fact that the specification disclosed human TNF-α protein, and despite the disclosure of the
structures of more than one species of antibody related to the genus, the court ruled that that
the generic antibody claims at issue were invalid for lack of written description. The fact pattern
is similar in the instant case. As in the court case, the instant claims recite a genus of
antibodies that have affinity for a specific antigen and have a desirable special property, i.e.,
ability to detect and assess liver cancer.
Following the finding in Centocor, the instant claims are found to lack adequate written
description. Similarly, in Juno Therapeutics, Inc., Sloan Kettering Institute for Cancer Research
v. Kite Pharma, Inc. (Case 2020-1758, CAFC August 2021), the court found that the disclosure
of two antibody products (scFv molecules) was insufficient to support written description for the
claimed genera, specifying that the specification at issue failed to disclose “structural features
common to the members of the genus to support that the inventors possessed the claimed
invention;” i.e., the specification and evidence of record failed to provide a structure -function
correlation. In the instant case, there is also no evidence of a structure-function correlation for
the antibodies, and thus the claims are properly rejected for lack of adequate written
description.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 3-8 are rejected under 35 U.S.C. 101 because the claimed method is directed towards a judicial of an abstract idea and laws of nature/natural phenomena without significantly more.
Step 1
Claims 3-8 are to a statutory category of a method of detecting naturally occurring biomarkers and correlating the biomarkers to diseases.
Step 2A prong 1: Does the claim recite a judicial exception?
The claims recite methods for observing the law of nature of a naturally occurring biomarker, HNE-generated calprotectin, and correlating the detection of HNE-generated calprotectin with diseases. The correlation between biomarkers and the presence of medical conditions is naturally occurring.
Step 2A prong 2: Does the claim recite additional elements that integrate the exception into a practical application?
Regarding the method of using the judicial exception, the data gathering steps do not add a meaningful limitation to the methods as they are insignificant extra-solution or mere data gathering steps.
Step 2B:
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claimed elements when considered separately and in combination, do not add significantly more to the exceptions. The natural law/phenomenon is analogous to the correlation of biomarkers found ineligible by the courts, for example, in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012), Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017) (Using well -known standard laboratory techniques to detect enzyme levels in a bodily sample such as blood or plasma), and Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015) (ineligible claims were directed to a method of detecting paternally inherited cell free fetal DNA, which is naturally occurring in maternal blood).
Regarding claim 3, the method of detecting and/or monitoring the progress of and/or determining the status or severity of a disease in a patient, wherein the disease is a disease characterized by or exhibiting inflammation, the method comprising contacting a biofluid sample obtained from said patient with the monoclonal antibody, detecting and determining the amount of binding between the monoclonal antibody and peptides in the sample, and correlating said amount of binding with values associated with normal healthy subjects and/or with values associated with a known status or severity of the disease and/or with values obtained from said patient at a previous time point and/or with a predetermined cut-off value is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Regarding claim 4, wherein the disease is an inflammatory driven disease is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Regarding claim 5, wherein the disease is inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, psoriasis arthritis, ankylosing spondylitis, osteoarthritis is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Regarding claim 6, wherein the disease is chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF) is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Regarding claim 7, wherein the disease is a cancer is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Regarding claim 8, wherein the disease is metastatic melanoma, small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) is directed towards judicial exceptions (i.e., law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Thus, claims 3-8 are rejected under 35 USC 101.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Grantham et al., “Myeloperoxidase-dependent Lipid Peroxidation Promotes the Oxidative Modification of Cytosolic Proteins in Phagocytic Neutrophils” (2015) teaches an immunoassay for detecting calprotectin in a method comprising contacting a human biofluid sample with a monoclonal antibody, and detecting the binding between the monoclonal antibody and the calprotectin.
While Grantham does use the abbreviations HNE, they are referring to 4-hydroxynonenal 3, which is different from the human neutrophil elastase (HNE) referred to in the instant application.
Grantham is silent towards a HNE-generated fragment of calprotectin and an antibody that specifically recognizes and binds to an HNE-generated neo-epitope consisting of an N-terminus or C-terminus sequence of the HNE-generated fragment of calprotectin.
Parekh et al., (US20170108511A1) (03/02/2015) teaches an immunoassay for detecting calprotectin and HNE in a method comprising contacting a human biofluid sample with a monoclonal antibody, and detecting the binding between the monoclonal antibody and the calprotectin.
While Parekh mentions that the antibody may comprise suitable amino acids at or near the N and C terminus to facilitate linkage to the scaffold molecules, Parekh is silent towards an antibody specifically recognizing and binding to the HNE-generated neo-epitope consisting of an N-terminus or C-terminus sequence of the HNE-generated fragment of calprotectin. Further, Parekh is silent towards the calprotectin being an HNE-generated fragment.
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/MCKENZIE A DUNN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678