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 .
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.
DETAILED ACTION
This action is in response to claim amendments filed 8/22/23. Claims 1-14 are pending and under examination.
Drawings
Color drawings have been submitted without a corresponding petition to accept color drawings.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 7 and 9 are objected to because of the following informalities: there is no conjunction at the end of the list of method steps. While the meaning is clear—all steps are meant to be practiced—there should still be an “and” prior to the last step. Appropriate correction is required.
Claims 9, 10, 13 and 14 is objected to because of the following informalities: there is no conjunction at the end of the list. The list is a Markush claim and so either “and” or “or” would properly designate these as alternatives (claim is not indefinite), but there should still be a conjunction to end the list. Appropriate correction is required.
Claim 13 is objected to because of the following informalities: the claim recites “wherein the disease selected from”; there appears to be a word missing, e.g., “wherein the disease is selected from”. Appropriate 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.
Claims 1-11 and 13-14 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.
Claim 1 lists options a-f. There is no conjunction before the last item on the list. In one interpretation, a-f are required (“and f”) but in another they are alternatives (“or f”). These are not clearly recited as a Markush group and so, unlike a claim such as claim 9, the use of “and” or “or” is not equivalent but rather alters the scope of the claim.
Dependent claims do not correct this deficiency.
Further, claim 1 recites sequences “more than 90%” identity to the sequences. However, SEQ ID NO: 3 is only 5 amino acids. The scope of this claim is unclear because even a single amino acid change results in less than 90% sequence identity and so it is unclear what limitations this additional phrase is meant to imply. SEQ ID NOs: 7 and 8 have the same issue.
Therefore, claims 1-11 and 13-14 are indefinite. The broadest reasonable interpretation of this claim is to interpret the elements with “or”.
Claim 13 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.
Claim 13 recites the limitation "wherein said disease" in line 8. There is insufficient antecedent basis for this limitation in the claim. There are eleven (11) previous recitations of “disease” and so it is unclear which of these “disease” recitations is meant to be “said disease”.
Therefore, claim 13 is indefinite.
Claims 3, 9, 10, 13, and 14 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 claims recite “the group comprising”, which is an example of indefinite Markush group language in MPEP §2173.05(h): “If a Markush grouping requires…selected from the group comprising…the claim should generally be rejected under 35 USC 112(b) as indefinite”. A Markush grouping must be closed; use of open language such as “comprising” renders the claim indefinite because it is unclear what other alternatives might be in the list.
Claim 3 is further indefinite for the recitation that the antibody is a “peptide”. There is no single art-recognized definition of the term. Cancer (form 892) defines a peptide as any molecule that contains two or more amino acids, which includes both polypeptides and proteins. The limitations of claim 1 already require at least two amino acids and so every embodiment of claim 1 already meets the limitations of a peptide. The specification does not have a special definition of the term nor does the specification provide guidance as to the metes and bounds of this term. While clearly intended to be a limitation, it is not clear what that limitation is meant to be.
Therefore, claims 3, 9, 10, 13, and 14 are indefinite.
Claim 6 is 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.
Claim 6 recites the limitation "the recombinant nucleic acid molecule" in line 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 6 does not recite “a recombinant nucleic acid molecule”, nor do any of the claims from which claim 6 depends.
Therefore, claim 6 is indefinite.
Claim 12 is 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.
Claim 12 recites a fragment that “consists of” an amino acid sequence “comprised between” certain residues. Using closed language (consists of) followed by open language (comprised) leads to indefiniteness of the claim scope. The closed language of “consists of” excludes any additional elements; however, “comprising” or “comprised” is open language that allows for the addition of any non-recited elements.
The claim also recites “an amino acid sequence”, which refers to any subsequence of the recited residues, e.g., AR is “an amino acid sequence” in residues A1-L48. However, the claims also recite “or a segment thereof”. It is unclear if this limitation means that a single amino acid is encompassed by the claims, e.g., “A” is a segment of the sequence AR.
Therefore, claim 12 is indefinite.
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 1-11 and 13-14 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.
Claim 1 is directed to any antibody that specifically binds a C-terminal fragment of cleaved histone H3, structurally defined by being 90% identical to a single CDR.
While antibodies generally share certain characteristics such as Fc regions or hinge regions, 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 (the cleaved histone H3) and envisage 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, 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. As a further example, see Chen (cited on form 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.
Even in an interpretation where all six CDRs claimed are required, the claims encompass mutations of 10%. As above, single changes to one CDR can radically and unpredictably alter binding properties of an antibody. This is further supported by Koenig (form 892), which provides a large mutation analysis study where each amino acid in both variable regions is substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, showing both reduced affinity and a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. The specification discloses only a single antibody and provides no guidance or examples of such mutations. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses the antibody 3D9, which comprises sequences 100% identical to SEQ ID NOs: 3-8. However, as discussed above, without any way to determine how broad the genus of such antibodies is, there is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of this specific antibody 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 that are 90% identical to the claimed sequences.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. MPEP 2163 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 nan 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”.
As further evidence, WO2018237338 (form 892) discloses an antibody with an identical CDR-L2 (seq id no: 226), yet this antibody binds α-synuclein, not histone H3. Thus, even being 100% identical at a CDR is insufficient to define the binding properties without the additional five CDRs, so altering those CDRs by 10% would also not be reasonably expected to preserve binding because it is the exact sequences of each of the six CDRs which defines such binding.
Claims such as claim 2 require more amino acids; however, the 90% identity limitation includes changes to the CDRs and so have the same deficiencies.
One could not envisage which portions of the CDRs are necessary to impart the claimed binding properties or which could be mutated without affecting such properties, nor does the instant specification provide guidance to this effect. As such, the disclosure of one antibody sequence does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequence of six CDRs is required.
Therefore, claims 1-11 and 13-14 do not meet the written description requirement.
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.
Claims 13-14 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 13 and 14 are directed to a kit that comprises the antibody of claim 1. There is no special definition of “kit” and so the preamble of the claim does not impart any limitations on the claim. Further, the “for assessing disease” and the specification of those diseases is related to an intended use. This use also is recited in the preamble and does not impart any specific limitations. When considering the claim as a whole, there are no additional limitations in claims 13 or 14 compared to claim 1 and so these claims fail to further limit the claim.
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.
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.
Claim 12 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A prong 1. Claim 12 is a fragment of histone H3 and falls within the statutory category of a composition.
Step 2A, prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2. In this case, the specification states that the claimed fragment is a purified fragment of human H3 (p.1). There is no evidence that the sequence has been altered from the naturally occurring human sequence and so the evidence supports the claimed sequence being a naturally occurring sequence. The specification also suggests that the cleavage at 48/49 of H3 is a natural occurrence (p.2). Further, the broadest reasonable interpretation of the claim is a segment of a sequence, which encompasses single amino acids. Alanine is within the scope of the claims and the Examiner takes Official Notice that alanine is a naturally occurring amino acid.
Step 2A, prong 2: Prong 2 requires the Examiner to evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception and, if not, proceed to step 2B. In order to integrate the recited judicial exception into a practical application, the claim will apply, rely on, or use the judicial exception that imposes a meaningful limit such that the claim is more than a drafting effort to monopolize the judicial exception. Examiners evaluate integration by identifying additional elements in the claim beyond the judicial exception and evaluating those elements individually and in combination to determine whether they integrate the exception in to a practical application. Examples that have been found by the Courts in which the exception was not integrated into a practical application include:
Mere instructions to implement an abstract idea on a computer
Adding generic instructions that the judicial exception should be used ("apply it")
Adding insignificant extrasolution activity to the exception ("mere data gathering")
Generally linking the use of the exception to a particular technological environment or field of use
In this case, there are no additional elements to consider.
Step 2B: Where a claim does not integrate the exception, a claim may nevertheless be patent eligible, for example where additional elements are “significantly more” than the exception such that the additional elements were unconventional in combination. Considerations include whether or not the claim adds a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; or simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
In this case, there are no additional elements to consider.
Therefore, claim 12 is not patent eligible.
Claim Rejections - 35 USC § 102
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) 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Vossaert (IDS 8/22/23 citation 2).
Regarding claim 12, Vossaert teaches human histone H3 cleaved at residues A21, R26, and 31 (abstract). This sequence is the same as instant SEQ ID NO:25 (figure 4). This disclosure therefore meets the limitations of a human histone H3 cleaved at site L48R49, where the fragment consists of the amino acids 1-21, 1-26, or 1-31. Note that while Vossaert does not teach H3 cleaved at 48/49, the segment disclosed in Vossaert is structurally identical to instant SEQ ID NO: 25 residues 1-31, which is therefore within the scope of the claims as a shorter fragment is not structurally altered by previous cleavage events that are not included in the final sequence.
Therefore, claim 12 is anticipated.
Conclusion
Claim 9 recites “said disease is associated with NET formation”. This is not an art-recognized class of diseases. However, the claim also recites “said disease” is selected from a group of other classes which generally are art-recognized, e.g., neurological disease, viral infection [disease], and cancer [disease]. As both “said disease” must refer to the same disease, these categories are also limitations of the NET formation diseases. As such, the genus is considered described.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ADAM M WEIDNER whose telephone number is (571)272-3045. The examiner can normally be reached M-T 9-18; W-R 9-15.
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/Adam Weidner/ Primary Examiner, Art Unit 1675