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 .
DETAILED ACTION
Claims 1-10, 12, 13, 16 and 17 are pending and under consideration.
Priority
It is acknowledged that this application is a 371 of International application of PCT/EP2022/052085 filed January 28, 2022, which claims the benefit of priority to Foreign application EP21305115.4 filed January 29, 2021. It is noted, however, that applicant has not filed a certified copy of the EP21305115.4 application as required by 37 CFR 1.55.
Information Disclosure Statement
The Information Disclosure Statement filed on 07/06/2023 has been considered and entered by examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 1 is objected to because of the following informalities: “VLA-4” should be “very late antigen-4 (VLA-4)”. Appropriate correction is required.
Claim 10 is objected to because of the following informalities: “PML” should be “progressive multifocal leukoencephalopathy (PML)”. 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.
Claim 13 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 13 recites “calculating a score and comparing the score …between said score …” which renders the claim indefinite. Claim 13 depends on claim 1 which recites a step of determining the abundance of Phyllobacterium. It is unclear whether the score recited by claim 13 is a score of the determined abundance of Phyllobacterium or a score of other parameters unrelated to the determined abundance of Phyllobacterium.
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 1-10, 12, 13, 16 and 17 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. This is a WRITTEN DESCRIPTION rejection.
The instant claims are drawn to a method of treating a patient with a VLA-antagonist comprising i) determining the abundance of Phyllobacterium in a biological sample obtained from the patient, and ii) administering a therapeutically effective amount of the VLA-4 antagonist to a patient identified as having an abundance of Phyllobacterium that is lower than a corresponding reference value. The method is based on the association between the abundance of Phyllobacterium and the risk of developing PML in a very specific patient population under a very specific VLA-antagonist treatment (See Example of the instant Specification). However, given Broadest Reasonable Interpretation (BRI), these claims encompass: 1) a broad genus of patients which may have different disease conditions, harbor different haplotype, have different previous treatments and have different JC virus status; 2) a broad genus of VLA-4 antagonists which may have different structures (e.g. small molecule, peptide, antibody, oligonucleotide, genome editing system, also see paragraphs [0016-0019] of the instant publication US 2024/0301512 A1). These compounds vary significantly, have different structures and physical/chemical properties, and function through different mechanisms and may have different therapeutic activity/property (such as resulting in PML). Thus, the specification lacks written description support for the broadly claimed genera.
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. (See Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, especially page 1106 3rd column). 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. MPEP 2163 II.A.3a.ii.
Regarding the treating a patient which may have different disease conditions, harbor different haplotype, have different previous treatments and have different JC virus status, it is well known in the art that the therapeutic effects for different disease conditions of a drug is generally unpredictable. As evidenced by the instant specification, the association between the abundance of Phyllobacterium and the risk of developing PML was only observed in the patients harboring a non-DRB1*1501 HLA-DR2 haplotype, but not in patients with DRB1*1501 HLA-DR2 haplotype ([0041], [0047], Figs. 1A and 1B, and Example of the instant publication US 2024/0301512 A1). Thus, one of ordinary skill in the art would not be able to readily visualize/recognize in which patient population the association between the abundance of Phyllobacterium and the risk of developing PML occurs as observed in relapsing remitting MS patients previously treated with NTZ, JC virus-positive with no HLA-DRB1*1501 haplotype as shown in the instant Example.
Regarding broadly claimed VLA-4 antagonists and the risk of developing PML, Kanda (Kanda et al., Clinical and Experimental Neuroimmunology 5 (Suppl 1), (2014) 28-34, Publication Year: 2014) teaches that NTZ is widely accepted as a potent tool for treating relapsing-remitting MS (Abstract). However, the risk of a potentially PML should always be kept in mind for NTZ treatment (page 30, col. 1). Kanda teaches that the factors associated with the risk of developing PML are 1) the JCV antibody status; 2) previous use of immunosuppressants; and 3) duration of NTZ therapy. JCV negative patients rarely suffer from PML (page 30, col. 2). In addition, different VAL-4 antagonists may have different structures, work through different mechanisms, have different specificity and potency. Thus, other VAL-4 antagonists may have different therapeutic properties compared with NTZ. For example, Firategrast (an orally active VAL-4 antagonist) has a shorter half-life than NTZ (2.5-4.5 hr vs 11 days). In a phase II clinical trial including 343 patients, no cases of PML or evidence of JC virus reactivation were identified during the 76 weeks of the trial period (§ Firategrast on page 31 of Kanda). Thus, the abundance of Phyllobacterium may not be associated with the therapeutic outcome of a Firategrast therapy and risk of developing PML.
In addition, as evidenced by claim 7 and [0019] of the instant publication US 2024/0301512 A1, the VLA-4 antagonists encompass a broad genus of antibodies which directed against VLA-4 or a ligand of VLA-4. These antibodies would have different binding targets and/or properties. Based on the teachings of the specification (see the following paragraph), one of ordinary skill would not expect that the therapeutic outcome of all antibodies would be associated with the abundance of Phyllobacterium in all patients.
In view of above, the instant specification discloses that Natalizumab (NTZ) is associated with the risk of progressive multifocal leukoencephalopathy (PML), an infection caused by the John Cunningham (JC) virus (Abstract). In a prospective study including 625 relapsing remitting MS patients previously treated with NTZ, among the JC virus-positive patients with no HLA-DRB1*1501 haplotype, there is a significant and positive association (
p
=
0.02
) between the abundance of Phyllobacterium and the presence and/or the development of PML, whereas no association was observed in patients with HLA-DRB1*1501 haplotype ([0041], [0047], Figs. 1A and 1B, and Example of the instant publication US 2024/0301512 A1). Thus, the specification has established a correlation between the abundance of Phyllobacterium and the risk of developing PML in a very specific patient population and a very specific VLA-antagonist treatment. The correlation of the abundance of Phyllobacterium and the therapeutic outcome of a VLA-4 antagonist has not been established for other disease conditions, other patient population and/or other VLA-4 antagonists.
In summary, the ordinary artisan could reasonably conclude based on a survey of the data shown in the instant specification in support of the breadth and scope of the instant claimed methods that Applicants were not in possession of the innumerable VLA-4 antagonists which can be used for treating all patients in the claimed methods. Taken together, the instant specification has not provided a sufficient description for the claimed invention.
Claims 1-10, 12, 13, 16 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
a method of treating a patient with a VLA-antagonist comprising i) determining the abundance of Phyllobacterium in a biological sample obtained from the patient, and ii) administering a therapeutically effective amount of the VLA-4 antagonist to a patient identified as having an abundance of Phyllobacterium that is lower than a corresponding reference value, wherein the patient has relapsing remitting multiple sclerosis (MS), is JC virus positive, and has been treated with Natalizumab (NTZ), wherein the patient harbors a non-DRB1*1501 HLA-DR2 haplotype, wherein the sample is a blood sample, and wherein the VLA-4 antagonist is natalizumab;
does not reasonably provide enablement for:
a method of treating a patient with a VLA-antagonist comprising i) determining the abundance of Phyllobacterium in a biological sample obtained from the patient, and ii) administering a therapeutically effective amount of the VLA-4 antagonist to a patient identified as having an abundance of Phyllobacterium that is lower than a corresponding reference value.
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/or use the invention commensurate in scope with these claims. This is a SCOPE OF ENABLEMENT rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The instant claims are drawn to a method of treating a patient with a VLA-antagonist comprising i) determining the abundance of Phyllobacterium in a biological sample obtained from the patient, and ii) administering a therapeutically effective amount of the VLA-4 antagonist to a patient identified as having an abundance of Phyllobacterium that is lower than a corresponding reference value. The method is based on the association between the abundance of Phyllobacterium and the risk of developing PML in a very specific patient population under a very specific VLA-antagonist treatment (See Example of the instant Specification). Given Broadest Reasonable Interpretation (BRI), these claims encompass: 1) a broad genus of patients which may have different disease conditions, harbor different haplotype, have different previous treatments and have different JC virus status; 2) a broad genus of VLA-4 antagonists which may have different structures (e.g. small molecule, peptide, antibody, oligonucleotide, genome editing system, also see paragraphs [0016-0019] of the instant publication US 2024/0301512 A1). These compounds vary significantly, have different structures and physical/chemical properties, and function through different mechanisms and may have different therapeutic activity/property (such as resulting in PML).
The instant specification discloses that Natalizumab (NTZ) is associated with the risk of progressive multifocal leukoencephalopathy (PML), an infection caused by the John Cunningham (JC) virus (Abstract). In a prospective study including 625 relapsing remitting MS patients previously treated with NTZ, among the JC virus-positive patients with no HLA-DRB1*1501 haplotype, there is a significant and positive association (
p
=
0.02
) between the abundance of Phyllobacterium and the presence and/or the development of PML, whereas no association was observed in patients with HLA-DRB1*1501 haplotype ([0041], [0047], Figs. 1A and 1B, and Example of the instant publication US 2024/0301512 A1). Thus, the specification has established a correlation between the abundance of Phyllobacterium and the risk of developing PML in a very specific patient population and a very specific VLA-antagonist treatment. The correlation of the abundance of Phyllobacterium and the therapeutic outcome of a VLA-4 antagonist has not been established for other conditions, other patient population and/or other VLA-4 antagonists.
Kanda (Kanda et al., Clinical and Experimental Neuroimmunology 5 (Suppl 1), (2014) 28-34, Publication Year: 2014) teaches that NTZ is widely accepted as a potent tool for treating relapsing-remitting MS (Abstract). However, the risk of a potentially PML should always be kept in mind for NTZ treatment (page 30, col. 1). Kanda teaches that the factors associated with the risk of developing PML are 1) the JCV antibody status; 2) previous use of immunosuppressants; and 3) duration of NTZ therapy. JCV negative patients rarely suffer from PML (page 30, col. 2). In addition, different VAL-4 antagonists may have different structures, work through different mechanisms, have different specificity and potency. Thus, other VAL-4 antagonists may have different therapeutic properties compared with NTZ. For example, Firategrast (an orally active VAL-4 antagonist) with a shorter half-life than NTZ (2.5-4.5 hr vs 11 days). In a phase II clinical trial including 343 patients, no cases of PML or evidence of JC virus reactivation were identified during the 76 weeks of the trial period (§ Firategrast on page 31 of Kanda). Thus, the abundance of Phyllobacterium may not be relevant to the therapeutic outcome of a Firategrast therapy and risk of developing PML.
It is well known that the art of immunotherapy is highly unpredictable in general. As evidenced by the instant specification, the association between the abundance of Phyllobacterium and the risk of developing PML was only observed in the patients harboring a non-DRB1*1501 HLA-DR2 haplotype, but not in patients with DRB1*1501 HLA-DR2 haplotype ([0041], [0047], Figs. 1A and 1B, and Example of the instant publication US 2024/0301512 A1).
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. As set forth above, the instant specification does not represent the substantial variety covered by the genus of patients and/or VLA-4 antagonists covered by the claims, the instant specification has not established the correlation between the abundance of Phyllobacterium and the risk of developing PML in other patient populations with other VLA-4 targeted therapy. Therefore, there is no enough guidance on how to make/use the invention commensurate in scope with these claims.
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general
ideas that may or may not be workable."
The specification and prior art provide insufficient guidance with regard to these issues and provides insufficient working examples which would provide guidance to one skilled in the art and no evidence has been provided which would allow one of skill in the art to predict that the invention will function as contemplated or claimed with a reasonable expectation of success. For the above reasons, it appears that undue
experimentation would be required to practice the claimed invention.
Due to the large quantity of experimentation necessary to test the use of VLA-4 antagonists and all patients encompassed by the claims; the lack of direction/guidance presented in the specification and prior arts regarding to the association between the abundance of Phyllobacterium and the outcome of a VLA-4 antagonist treatment (e.g. the risk of developing PML); the state of the prior art which establishes the unpredictability immunotherapy in general; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Related Prior Art
Bloomgren (WO 2014/193804 A1, Publication Date: 12/04/2014, cited in IDS of 07/26/2023) teaches the anti-VLA-4 antibody therapeutic natalizumab (NTZ) is indicated to treat relapsing forms of multiple sclerosis (MS). Natalizumab treatment, however, is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection caused by the JC virus (JCV). PML occurs primarily in immunocompromised individuals and in patients receiving certain immunomodulatory therapies, including natalizumab (page 1, lines 11-20). Bloomgren teaches a method of evaluating a patient’s risk of developing PML, the method comprising: determining a JCV antibody titer in a biological sample from the patient, wherein the patient has a negative prior immunosuppressant exposure classification; wherein if the titer is determined to be above a pre-determined level and wherein if the titer is determined to be at or below a pre-determined level, the patient is determined to be at a low risk of developing PML (claim 1). Bloomgren teaches that if the patient is determined to be at lower risk of developing PML, then the patient is classified as being suitable for treatment with an anti-VLA-4 therapy, such as NTZ therapy (claims 17-19). Although Bloomgren teaches evaluating risk of developing PML and treating patients with lower risk of developing PML with NTZ therapy, Bloomgren does not teach using the abundance of Phyllobacterium as an indicator for the risk of developing PML under anti-VLA-4 therapy (such as NTZ therapy).
Chalkley (Chalkley et al., Curr Neurol Neurosci Rep (2013) 13: 408, Publication Date: 10/18/2013, cited in IDS of 07/26/2023) teaches that three indicators have been demonstrated to enable stratification of risk with natalizumab use. These include JCV seropositivity, duration of natalizumab use, and preceding use of any immunosuppressive therapy, regardless of duration of and time from last treatment with the latter (page 5, § Risk Mitigation Strategies, and Fig. 2). However, Chalkley does not teach using the abundance of Phyllobacterium as an indicator for the risk of developing PML under anti-VLA-4 therapy (such as NTZ therapy).
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642