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 .
Claim Status
Applicant’s preliminary amendments and remarks, filed 05/11/2023, are acknowledged.
Claims 1-14 are pending.
As such, claims 1-14 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
DETAILED ACTION
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/113,864 and 63/142,968, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Present claims 9 and 12 are drawn to a method wherein the therapeutically effective amount administered SC during the chronic phase is about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg, more preferably about 300 mg, still more preferably 300 mg. Provisional applications 63/113,864 and 63/142,968 fail to disclose of the instantly claimed chronic phase amounts. Accordingly, claims 9 and 12 are not entitled to the benefit of these prior applications. However, Examiner acknowledges that provisional applications 63/113,864 and 63/142,968, filed on 11/14/2020 and 01/28/2021, respectively, do disclose of the instantly claimed methods as recited in instant claims 1-8, 10-11, and 13-14. Therefore, instant claims 1-8, 10-11, and 13-14 have a priority date of 11/14/2020.
If Applicant disagrees with the examiner’s factual determination above, Applicant should provide evidence as to where the relevant features were disclosed in the earlier-filed application. This could be accomplished, for example, by pointing to specific pages or figures within the provisional application that disclose the now-claimed invention.
Specification
The disclosure is objected to because of the following informalities:
Para. [0012] is missing a period (.) at the end of the paragraph.
[0079] – [0088] and Tables 2-3: decimals should be lowered (e.g., “4·0” should read “4.0”).
[0079]: “randomisation” should read “randomization”.
Table 2: “Normalised” should read “Normalized”.
[0086]: “enrolment” should read “enrollment”.
Appropriate correction is required.
The use of the term TYSABRI®, BIOGEN®, and STRATIFY JCV™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1-14 are objected to because of the following informalities:
Claims 1-2 and 4: “VLA-4” is an acronym and/or abbreviation which should be spelled out on first occurrence.
Claims 10 and 13-14: “SID” and “EID” are acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 14: “sVCAM” and “Nf-L” are acronyms and/or abbreviations which should be spelled out on first occurrence.
Claim 14, line 7: “the individual” should read “the patient”.
Appropriate correction is required.
Claims 5-9 and 12-13 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only and/or cannot depend from any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claim Interpretation
Claim 14 recite the transitional phrase “having”, the scope of which is not defined by the specification. As such, according to MPEP 2111.03(IV), the term will be interpreted as an open-ended transitional term, similar to the transitional phrase “comprising”. For example, the structure recited in the claims can comprise additional, unrecited elements.
Examiner acknowledges that the term “biphasic dosing regimen” refers to the administration of natalizumab in at least two phases, e.g., an induction phase and a chronic phase (see [0041] of the specification).
Further, Examiner acknowledges that the term “extended interval dosing (EID)” refers to the administration of natalizumab at intervals that extend beyond the “standard interval dosing (SID)” dosing schedule of 300 mg every 4 weeks. An EID schedule should not exceed 12 doses of natalizumab within a 12-month period (one month equals 30 days), and typically does not exceed 11 or 10 doses within a 12-month period (one month equals 30 days). Thus, a SID schedule should exceed 10 doses of natalizumab within a 12-month period, and typically exceeds 11 or 12 doses in a 12-month period. See specification para. [0042].
Claim Rejections - 35 USC § 112(b)
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 1-4, 10-11, 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 1 and 2 recite the broad recitation “for 10 to 14 months”, and the claims also recite “at least 12 months” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term “preferably” in claims 1-2 and 10-11 renders the claims indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(d).
Claims 1 and 2 recite the limitation "the anti-VLA-4 therapy" in line 6. There is insufficient antecedent basis for this limitation in the claim.
The phrase “suspected of suffering from” in claim 2 is a relative term which renders the claim indefinite. The phrase “suspected of suffering from” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The claims nor specification disclose what criteria or symptoms one must possess in order to be “suspected of suffering from” multiple sclerosis. As such, one would not be apprised as to what is encompassed by the phrase thus making the claim indefinite. Therefore, claim 2 and its dependent claims are rejected.
Claim 10 recites “the method comprising administering the natalizumab therapy subcutaneously on an SID schedule for an induction phase of at least 12 months, and then administering the natalizumab therapy on an EID schedule of at least 6-week intervals chronically thereafter”. It is unclear if the “subcutaneously” is only in reference to the SID schedule or if the term is also encompassing the EID schedule.
Further, claim 10 recites “an SID schedule for an induction phase of at least 12 months, and then administering the natalizumab therapy on an EID schedule of at least 6-week intervals chronically thereafter”. As stated above, the term “extended interval dosing (EID)” refers to the administration of natalizumab at intervals that extend beyond the “standard interval dosing (SID)” dosing schedule of 300 mg every 4 weeks. An EID schedule should not exceed 12 doses of natalizumab within a 12-month period (one month equals 30 days), and typically does not exceed 11 or 10 doses within a 12-month period (one month equals 30 days). Thus, a SID schedule should exceed 10 doses of natalizumab within a 12-month period, and typically exceeds 11 or 12 doses in a 12-month period. See specification para. [0042]. The claim indicates that the SID schedule is “at least 12 months” which under the broadest reasonable interpretation (BRI) that means 12 months or more, but the specification states that the SID schedule is a 12-month timeframe. Thus, it is unclear what is the actual timeline for SID schedule. As such, claim 10 and its dependent claims are rejected.
Claim 11 recites the limitation "the chronic phase" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites the limitation "the induction phase" in line 5. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites a “first biological sample” and a “second biological sample”. It is unclear if these biological samples are from the same source (e.g., both first and second are blood, tissue, urine, etc.), or if the biological samples are from different sources.
Claim Rejections - 35 USC § 112(a) Written Description
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 1-4, 10-11, and 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a method of reducing pathological inflammation in a patient in need thereof comprising administering a therapeutically effective amount of an anti-VLA-4 antibody to the patient in a biphasic dosing regimen, wherein the biphasic regimen comprises an induction phase comprising administration of the anti-VLA-4 antibody once a month for 10 to 14 months, preferably at least 12 months, followed by a chronic phase comprising administration of the anti-VLA-4 therapy once every 5, 6, 7 or 8 weeks, preferably wherein at least one phase of the biphasic protocol comprises subcutaneous (SC) administration.
Claim 2 is drawn to a method of reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis, comprising administering a therapeutically effective amount of an anti-VLA-4 antibody to the patient in a biphasic dosing regimen, wherein the biphasic regimen comprises an induction phase comprising administration of the anti-VLA-4 antibody once a month for 10 to 14 months, preferably at least 12 months, followed by a chronic phase comprising administration of the anti-VLA-4 therapy once every 5, 6, 7 or 8 weeks, preferably wherein at least one phase of the biphasic protocol comprises subcutaneous (SC) administration.
Claim 3 is drawn to the method of claim 1, wherein the pathological inflammation is caused by multiple sclerosis, and the therapeutically effective amount is sufficient to relieve symptoms of multiple sclerosis.
Claim 4 is drawn to the method of any one of claims 1-3, wherein the anti-VLA-4 antibody is natalizumab.
Claim 10 is drawn to a method of administering natalizumab to a patient in need thereof based on a biphasic dosing regimen, the method comprising administering the natalizumab therapy subcutaneously on an SID schedule for an induction phase of at least 12 months, and then administering the natalizumab therapy on an EID schedule of at least 6-week intervals chronically thereafter, wherein one or both and preferably both, treatment phases comprise SC administration.
Claim 11 is drawn to the method of claim 10, wherein the therapeutically effective amount administered during the induction phase and the chronic phase are the same; preferably wherein the therapeutically effective amount is 300 mg.
Claim 14 is drawn to a method for determining and/or monitoring the efficacy of a biphasic dosing protocol for natalizumab having an induction phase comprising an SID schedule and a chronic phase comprising an EID schedule in a patient in need thereof, the method comprising a) measuring a soluble molecule in a first biological sample obtained from the patient during the induction phase, wherein the soluble molecule is sVCAM and/or Nf-L; b) measuring the sVCAM and/or Nf-L in a second biological sample obtained from the individual during the chronic phase; c) determining whether there is an increase in the levels of the sVCAM and/or Nf-L above predetermined thresholds between the first and second samples, and d) in the event of an increase above one or both predetermined thresholds reverting said patient to an SID schedule or increasing the dose frequency of the EID schedule.
The specification discloses of the pharmacokinetics and pharmacodynamics of natalizumab every 4 following subcutaneous and intravenous administration (see Example 1). Single-dose PK/PD was collected over 8 weeks, with sampling at 4 hours and on days 1, 2, 3, 4, 7, 14, 21, 28, 35, 42, and 56; multi-dose trough PK/PD was collected for an additional 6 doses over 24 weeks (see [0068]). Steady-state natalizumab trough serum concentrations and alpha-4 integrin saturations over time for natalizumab 300, 350, 400, and 450 mg SC Q4W were simulated for 1000 subjects per SC dose and compared with the PK/PD profile of natalizumab 300 mg IV Q4W (see [0068]). The data support 300 mg SC dosing and predict that it will achieve efficacy similar to the currently approved 300 mg IV dosing (see [0070]).
Example 2 discloses the modeling and simulation comparison of PK and PD of natalizumab every 6 weeks following intravenous and subcutaneous dosing. Natalizumab 300 mg administered IV approximately every 6 weeks is associated with significantly lower risk of PML than natalizumab 300 mg IV dosing every 4 weeks (see [0071]). PK/PD results for patients who switched to Q6W dosing after 1 year of Q4W dosing (10,000 simulated subjects) were compared with observed interim PK/PD results for patients on the same dosing regimen in NOVA (see [0073]). The results predict that trough natalizumab concentration and alpha-4 integrin saturation will be similar for Q6W IV and SC dosing, suggesting that similar efficacy and safety profiles can be expected for IV and SC administration (see [0075]).
Example 3 discloses the comparison of switching to 6-week dosing of natalizumab versus remaining on 4-week dosing in patients with relapsing-remitting multiple sclerosis (RRMS): a randomized controlled study (NOVA). Patients with RRMS treated with natalizumab every 4-weeks who switch to extended interval dosing with an approximate dosing interval of every 6-weeks have significantly reduced risk of PML compared with patients on Q4W dosing (see [0076]). NOVA was a controlled, prospective, open-label, rater-blinded multinational study in patients from 89 sites treated with natalizumab 300 mg by intravenous infusion Q4W for ≥12 months who were randomized 1:1 to switch to natalizumab intravenous Q6W dosing or to continue Q4W treatment (see [0078]). The results of this study indicate that disease activity remains low in patients who switch to natalizumab Q6W after ≥1 year of stable Q4W treatment; the findings further suggest that a majority of patients stable on natalizumab Q4W dosing can switch to Q6W dosing with little or no clinically meaningful loss of efficacy (see [0089]).
Lastly, Example 4 discloses of the subject preference for SC versus IV route of natalizumab administration. Subjects who participated in the study disclosed in Example 3, receive natalizumab 300 mg by IV infusion once every 6 weeks (42 ± 7 days) for a period of 36 weeks and be randomized to an additional 48 weeks of crossover treatment comprising 24 weeks EID SC Q6W and 24 weeks EID IV Q6W (see [0093]). At the completion of their 48-week crossover treatment period, subjects receive a final dose of natalizumab 300 mg by SC injection or IV infusion at Week 156 with the route of administration being the subject’s choice, proceed to the 12-week follow-up period, and receive a follow-up safety phone call 12 weeks later (i.e., 24 weeks after the last dose of study treatment) before completing the study (see [0093]). Secondary endpoints are assessed between 6 months of SC treatment and 6 months of IV treatment in the randomized crossover period, and include: satisfaction with SC versus IV route of administration, comparison of drug preparation and administration time between SC and IV routes of natalizumab administration, evaluation of the safety and immunogenicity of SC versus IV routes of natalizumab administration, and analysis of the PK and PD of SC versus IV routes of natalizumab administration (see [0094]).
However, the specification fails to disclose that Applicant was in possession of the methods as claimed. First, the specification fails to disclose that Applicant was in possession of reducing any pathological inflammation in a patient with any disease or condition. Additionally, the specification fails to disclose that Applicant was in possession of the large genus of anti-VLA-4 antibodies as recited in the claims. The specification fails to disclose of a chronic phase/EID schedule wherein the anti-VLA-4 therapy/antibody is administered once every 5, 7, or 8 weeks as claimed. Lastly, the specification fails to disclose of a method of determining and/or monitoring the efficacy of a biphasic dosing protocol for natalizumab as recited in claim 14. Particularly, the specification fails to disclose of measuring sVCAM and/or Nf-L in a patient’s biological sample nor does the specification provide the predetermined threshold for one to determine whether levels have increased.
Although the specification discloses that trough natalizumab concentration and alpha-4 integrin saturation will be similar for Q6W IV and SC dosing suggesting that similar efficacy and safety profiles can be expected for IV and SC administration and that disease activity remains low in RRMS patients who switch to natalizumab Q6W after ≥1 year of stable Q4W treatment; the findings further suggest that a majority of patients stable on natalizumab Q4W dosing can switch to Q6W dosing with little or no clinically meaningful loss of efficacy, the claims are not limited to multiple sclerosis nor natalizumab, and are inclusive of any pathological inflammation and any anti-VLA-4 therapy/antibody. This indicates that there are hundreds, if not thousands, of possible methods of reducing pathological inflammation comprising administering any anti-VLA-4 antibody/therapy encompassed by the claims. Thus, the claims encompass a vast genus of disease-inhibitor treatments that have the claimed functions. However, the specification provides limited guidance on the structure and steps required for maintaining the claimed function(s). Further, the specification provides limited guidance on what the predetermined threshold for one to determine whether levels have increased. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of anti-VLA-4 therapies because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function. Furthermore, the specification fails to provide method steps that result in reducing any pathological inflammation in a patient with any disease or condition. Although the term antibody does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies/therapies and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of anti-VLA-4 therapies. The disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163).
The instant claims do not fully describe the structure of the anti-VLA-4 therapies to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of anti-VLA-4 therapies, claimed only by a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous anti-VLA-4 therapies had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of anti-VLA-4 therapies claimed only by a partial structure and functional characteristic(s). Thus the anti-VLA-4 therapies described by the instant claims encompasses an overly broad genus, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of anti-VLA-4 antibodies/therapies by the functions of targeting VLA-4. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
The art teaches the unpredictability of antibody-based immunotherapy. Christiansen et al (Mol Cancer Ther, 2004, 3:1493-1501) teach numerous factors that inhibit successful therapeutic application of antibodies including low or heterogeneous expression of target antigens by tumor cells, high background expression of target antigen on normal cells, host antibody immune responses to the antibodies themselves, insufficient antitumor response after antibody binding, as well as significant physical barriers preventing antibody binding or delivery to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers (abstract; p. 1493, col. 2; p. 1496, col. 1, last paragraph through p. 1498, col. 2). Topp et al (Journal of Controlled Release, 1998, 53:15-23) also teach the complications and unpredictability involved with treating tumors using antibody therapy. Topp et al teach that there are several barriers to successful delivery of antibody drugs to extravascular sites of action within target tissues: the antibody drugs must be absorbed into the blood stream, carried by the circulatory system to the capillaries in the target tissue, cross the capillary endothelial cells and the underlying basement membrane that supports the capillary structure and penetrate through the matrix of cells and extracellular components that comprises the tissue itself, bind to the cell surface receptor, initiate endocytosis, encounter possible drug degradation and drug release. Additional connective tissue barriers may also be encountered (p. 15, both columns; Figure 1). While some antibody drugs have been shown to be effective in vitro the results of clinical trials have been disappointing. The inability of the antibodies to penetrate the tumor mass could be a cause of this lack of clinical efficacy. Topp et al cautions against extrapolating in vitro results to in vivo therapy stating that the cell culture system has some limitations including a lack of well-developed extracellular matrix (“stroma”) that is present in many tumors. Normal components of tumor stroma include collagen, fibronectin and glycosaminoglycans (p. 21, col. 2). Given the unpredictable art of treating pathological inflammation in vivo using antibody therapy, compounded by the numerous forms of VLA-4 and unknown functions and receptors, one of skill in the art could not predictably treat PML in a patient known or suspected of suffering from multiple sclerosis in vivo comprising administering any antibody that binds VLA-4 as broadly claimed, other than antibody natalizumab.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed anti-VLA-4 therapies, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ... To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Regarding the encompassed anti-VLA-4 therapies that are antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and therapies that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies/therapies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed antibodies or therapies that are proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed anti-VLA-4 therapies could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all anti-VLA-4 therapies.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed anti-VLA-4 therapies. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). The specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of anti-VLA-4 antibodies/therapies as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 112(a) Enablement
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 1-3 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement
requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S.
261, 270 (1916) which postured the question: is the experimentation needed to practice the
invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858
F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does
not use the term "undue experimentation," it has been interpreted to require that the claimed
invention be enabled so that any person skilled in the art can make and use the invention without
undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence
to support a determination that a disclosure does not satisfy the enablement requirement and whether
any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content
of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant for this rejection are: (A) the breadth of the claims; (B) the nature of the invention; (E) the level of predictability in the art; (F) the amount of direction provided by the inventor; (G) the existence of working examples; and (H) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In regard to Wands factors (A) and (B), the breadth of the claims needed to enable the invention
is determined by whether the scope of enablement provided to one skilled in the art by the disclosure is
commensurate with the scope of protection sought in the claims. AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). The propriety of a rejection based upon the scope of a claim relative to the scope of the enablement concerns (1) how broad the claim is with respect to the disclosure and (2) whether one
skilled in the art could make and use the entire scope of the claimed invention without undue
experimentation.
The nature of the invention is a method of reducing pathological inflammation in a patient in need thereof or reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis, comprising administering a therapeutically effective amount of an anti-VLA-4 antibody to the patient in a biphasic dosing regimen, wherein the biphasic regimen comprises an induction phase comprising administration of the anti-VLA-4 antibody once a month for 10 to 14 months, preferably at least 12 months, followed by a chronic phase comprising administration of the anti-VLA-4 therapy once every 5, 6, 7 or 8 weeks, preferably wherein at least one phase of the biphasic protocol comprises subcutaneous (SC) administration. Therefore, the nature of the invention is a biochemical case, where there is natural unpredictability in performance of certain species other than those specifically enumerated; see MPEP § 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the functionality of the claimed method, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species may or may not work; see MPEP § 2164.03.
In regard to Wands factors (C), (D), and (E), the state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains and provides evidence for the degree of predictability in the art; see MPEP § 2164.05(a). The claims encompass reducing pathological inflammation in a patient in need thereof, including cancer patients, or reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis with a large genus of anti-VLA-4 antibodies. These cancers are highly heterogeneous at both the molecular and clinical level. Additionally, it is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
Additionally, Bally et al. (US Patent No. 5,595,756A, publication date: 01/21/1997) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1).
Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph).
Gura T (Science, 1997, 278(5340): 1041-1042, encloses 1-5) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph).
Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cell…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumors’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumor progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”.
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al. (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al. teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Beans also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al. teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al. teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers. In conclusion, the art provides evidence that heterogeneity in cancers can display unpredictability in response to the same treatment.
The art teaches the unpredictability of antibody-based immunotherapy. Christiansen et al (Mol Cancer Ther, 2004, 3:1493-1501) teach numerous factors that inhibit successful therapeutic application of antibodies including low or heterogeneous expression of target antigens by tumor cells, high background expression of target antigen on normal cells, host antibody immune responses to the antibodies themselves, insufficient antitumor response after antibody binding, as well as significant physical barriers preventing antibody binding or delivery to a solid tumor mass, including the vascular endothelium, stromal barriers, high interstitial pressure, and epithelial barriers (abstract; p. 1493, col. 2; p. 1496, col. 1, last paragraph through p. 1498, col. 2). Topp et al (Journal of Controlled Release, 1998, 53:15-23) also teach the complications and unpredictability involved with treating tumors using antibody therapy. Topp et al teach that there are several barriers to successful delivery of antibody drugs to extravascular sites of action within target tissues: the antibody drugs must be absorbed into the blood stream, carried by the circulatory system to the capillaries in the target tissue, cross the capillary endothelial cells and the underlying basement membrane that supports the capillary structure and penetrate through the matrix of cells and extracellular components that comprises the tissue itself, bind to the cell surface receptor, initiate endocytosis, encounter possible drug degradation and drug release. Additional connective tissue barriers may also be encountered (p. 15, both columns; Figure 1). While some antibody drugs have been shown to be effective in vitro the results of clinical trials have been disappointing. The inability of the antibodies to penetrate the tumor mass could be a cause of this lack of clinical efficacy. Topp et al cautions against extrapolating in vitro results to in vivo therapy stating that the cell culture system has some limitations including a lack of well-developed extracellular matrix (“stroma”) that is present in many tumors. Normal components of tumor stroma include collagen, fibronectin and glycosaminoglycans (p. 21, col. 2). Given the unpredictable art of treating pathological inflammation in vivo using antibody therapy, compounded by the numerous forms of VLA-4 and unknown functions and receptors, one of skill in the art could not predictably treat PML in a patient known or suspected of suffering from multiple sclerosis in vivo comprising administering any antibody that binds VLA-4 as broadly claimed, other than antibody natalizumab.
With respect to the autoimmune diseases, an autoimmune disease is a condition arising from an abnormal immune response to a normal body part. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. The cause is generally unknown. Examples include diabetes mellitus type 1, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, scleroderma, vitiligo, and systemic lupus erythematosus.
Blumberg et al. (Nat Med. (2012); 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3). It is important to remember that the claims are even broader than the field of autoimmune disorders, including diseases such as, for example, infectious diseases, neurodegenerative disease, ischemia/reperfusion injury and transplantation rejection which are beyond the scope of autoimmune disorders.
For example, Kramer et al (Neurotherapeutics (2022) 19:785–807) disclose that a remarkable number of monoclonal antibodies (mAbs) fail treatment of multiple sclerosis due to negative study results that were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons (see Abstract). Particularly, Kramer et al disclose of natalizumab, a recombinant humanized mAb directed against VLA-4 on leukocytes blocking adherence to the lumen of the endothelial BBB and transmigration of B and T lymphocytes, macrophages, and dendritic cells into the CNS and decreasing cerebral microglial activation (see pg. 797, right col.). Kramer et al disclose that natalizumab showed no treatment effect on the multi-component CDP, nor on its EDSS or 25TWT components, but reduced the disability progression of the upper limb component assessed by the 9HPT (see pg. 797, right col.). Natalizumab did not affect whole brain atrophy during part 1 of the study, and the incidence of AEs and SAEs did not differ between natalizumab and placebo in part 1 and between patients continuing natalizumab and those initiating natalizumab in part 2 of the study (see pg. 798, left col.). Kramer et al disclose that while natalizumab is highly efficacious therapy for the treatment of RRMS, it failed to demonstrate a significant effect on disability progression in SPMS in contrast to Siponimod in the EXPAND trial because Siponimod can cross the BBB in contrast to natalizumab (see pg. 798, left col.).
As such, the art indicates autoimmune diseases, specifically MS, can affect the efficacy of therapeutics used to treat it. Therefore, the art is unpredictable regarding treatment of all autoimmune diseases with a single compound or class of compounds.
In regard to Wands factors (F), (G) and (H), the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech
Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004).
The claims are drawn to a method of reducing pathological inflammation in a patient in need thereof or reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis.
The working examples provided by Applicant do not demonstrate a method of reducing all pathological inflammation in a patient in need thereof or reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis. Example 3 discloses the comparison of switching to 6-week dosing of natalizumab versus remaining on 4-week dosing in patients with relapsing-remitting multiple sclerosis (RRMS): a randomized controlled study (NOVA). Patients with RRMS treated with natalizumab every 4-weeks who switch to extended interval dosing with an approximate dosing interval of every 6-weeks have significantly reduced risk of PML compared with patients on Q4W dosing (see [0076]). The results of this study indicate that disease activity remains low in patients who switch to natalizumab Q6W after ≥1 year of stable Q4W treatment; the findings further suggest that a majority of patients stable on natalizumab Q4W dosing can switch to Q6W dosing with little or no clinically meaningful loss of efficacy (see [0089]). However, one case of asymptomatic PML occurred in the natalizumab Q6W treatment arm (Patient 2), with no cases in the Q4W group (see [0086]).
Because the specification only studied natalizumab in MS patients, one cannot assume that the method of reducing a vast variety of pathological inflammations with any anti-VLA-4 antibody will work similarly to the natalizumab-MS patients provided in the specification. In the absence of empirical determination, one skilled in the art would be subjected to undue experimentation to determine if the claimed method of reducing all pathological inflammation in a patient in need thereof or reducing progressive multifocal leukoencephalopathy (PML) in a patient known or suspected of suffering from multiple sclerosis would result in therapeutic response as recited in the claims.
Applicant is reminded that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent 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”. See Genentech, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 and 14 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Campbell et al (WO 2019/084335 A1; publication date: 05/02/2019).
Campbell et al is drawn to methods for reducing the risk of developing progressive multifocal leukemia in patients undergoing natalizumab therapy by switching to an extended interval dosing (EID) schedule (see Abstract). With respect to the instant biphasic regimen, Campbell et al disclose of a method of administering to a patient in need thereof a natalizumab therapy wherein the method comprises administering natalizumab therapy on an SID schedule for 12 months and then administering the natalizumab therapy on an EID schedule (at least 5 weeks and no more than 7 weeks) (see claims 41-47). The natalizumab therapy during the SID and EID schedule would be administered at the dosage of 300 mg (see claims 42 and 43). Campbell et al found that the EID schedule was associated with a reduction in the conditional risk of PML (see Tables 23 and 34; Examples 1-4 and 7).
With respect to instant claim 14, Campbell et al disclose of a method of reducing risk of developing PML in a subject, comprising: a. identifying a low PML risk subject who has been receiving natalizumab therapy on a SID schedule of 4-week intervals; b. determining whether the subject has switched from a low PML risk subject to a high PML risk subject during the natalizumab therapy; and c. if the subject has switched to a high PML risk subject, identifying the high PML risk subject for natalizumab therapy on an EID schedule of greater than 4-week intervals (e.g., at least 5-week intervals) (see pg. 108, lines 18-25). Particularly, Campbell et al disclose of detecting soluble vascular cell adhesion molecule 1 (sVCAM1) in serum, plasma, whole blood RNA, and PBMC samples (see pg. 64).
As such, the teachings of Campbell et al anticipate the present invention. Applicant is reminded that the term “preferably” in the instant claims renders the claims indefinite because it is unclear whether the limitations following the term are part of the claimed invention; thus, the limitations after the term were not considered.
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.
Claims 1-4, 10-11, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al (WO 2019/084335 A1; publication date: 05/02/2019) as applied to claims 1-3 and 14 above, and further in view of Plavina et al (The Journal of Clinical Pharmacology (2016)/Volume 56, Issue 10/pp. 1254-1262; Abstract only).
With respect to instant claims 1-4, 10-11, and 14, Campbell et al is drawn to methods for reducing the risk of developing progressive multifocal leukemia in patients undergoing natalizumab therapy by switching to an extended interval dosing (EID) schedule (see Abstract). With respect to the instant biphasic regimen, Campbell et al disclose of a method of administering to a patient in need thereof a natalizumab therapy wherein the method comprises administering natalizumab therapy on an SID schedule for 12 months and then administering the natalizumab therapy on an EID schedule (at least 5 weeks and no more than 7 weeks) (see claims 41-47). The natalizumab therapy during the SID and EID schedule would be administered at the dosage of 300 mg (see claims 42 and 43). Campbell et al found that the EID schedule was associated with a reduction in the conditional risk of PML (see Tables 23 and 34; Examples 1-4 and 7).
With respect to instant claim 14, Campbell et al disclose of a method of reducing risk of developing PML in a subject, comprising: a. identifying a low PML risk subject who has been receiving natalizumab therapy on a SID schedule of 4-week intervals; b. determining whether the subject has switched from a low PML risk subject to a high PML risk subject during the natalizumab therapy; and c. if the subject has switched to a high PML risk subject, identifying the high PML risk subject for natalizumab therapy on an EID schedule of greater than 4-week intervals (e.g., at least 5-week intervals) (see pg. 108, lines 18-25). Particularly, Campbell et al disclose of detecting soluble vascular cell adhesion molecule 1 (sVCAM1) in serum, plasma, whole blood RNA, and PBMC samples (see pg. 64).
Campbell et al fails to teach of administering natalizumab subcutaneously as recited in the instant claims. This is remedied by Plavina et al.
Plavina et al disclose of a randomized trial evaluating various administration routes of natalizumab in multiple sclerosis (see Title). The study compared the PK and PD of single SC or intramuscular (IM) 300-mg doses of natalizumab with IV 300-mg doses of natalizumab in patients with MS (see Abstract). Following SC or IM administration of natalizumab, peak serum concentrations were approximately 40% of those observed with IV administration and showed no major differences in elimination characteristics (see Abstract). The mean bioavailability relative to IV administration was 57.1% to 71.3% with SC administration and 48.7% with IM administration; mean trough serum concentrations were similar with SC or IV administration and lower with IM administration (see Abstract). Following single or multiple doses of natalizumab, PD response was comparable across administration routes and disease stages; no meaningful differences were observed across administration groups in the incidence or nature of overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or anti-natalizumab antibodies (see Abstract).
As such, it would have been obvious to combine the teachings of Campbell et al and Plavina et al to develop the claimed invention. One would be motivated to do so because Campbell et al found that incorporating an EID schedule has reduced PML in MS patients especially following an SID schedule. Further, one would consider subcutaneous administration of natalizumab compared to IV administration as taught by Campbell et al because Plavina et al disclose that SC administration demonstrated higher mean bioavailability than IV administration and there were no meaningful differences in overall adverse events, serious adverse events, administration site reactions, hypersensitivity reactions, or anti-natalizumab antibodies across the administration groups. As such, one would have a reasonable expectation that administering natalizumab subcutaneously would provide therapeutic benefit similarly, or even improved, compared to IV administration.
Further, Applicant’s attention is drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Although this passage does not specifically point to, for example, administration schedules and modes of drug administration, this passage points to numerous variables that affect the function of inventions, such as concentration of reagents and temperature ranges. Furthermore this passage indicates that the optimization of such variables is often obvious activity for one of ordinary skill in the art. It is submitted that the claimed modes of drug administration are akin to the variables discussed in the cited MPEP passage, because said modes of drug administration are optimizable variables that would affect at least the toxicity and/or efficacy, i.e., function, of the claimed invention. Given the “normal desire of scientists or artisans to improve upon what is already generally known,” it would have been prima facie obvious to one of ordinary skill in the art to optimize the claimed drug dosages, administration schedules, and treatment period, because such optimization would produce a more effective invention.
Also as set forth in MPEP 2144.05(II)(B), There is a Motivation to Optimize Result-Effective Variables:
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
In the instant case, the claims are drawn to administration schedules and modes of drug administration which achieve a recognized result, such as drug toxicity and/or therapeutic benefit. Accordingly the recited administration schedules and modes of drug administration are result-effective variables that achieve a recognized result, such as drug toxicity and/or therapeutic benefit for a patient with MS, and it is submitted that since one of ordinary skill in the art would have thus been motivated to determine the optimum or workable ranges of said variables, the administration schedules and modes of drug administration recited were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18/286,721
Claims 1, 3-4 and 10-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/286,721 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
With respect to claims 1, 3-4, and 10-11, the ‘721 application is drawn to a method of treating Radiologically Isolated Syndrome in a patient in need thereof comprising administering a therapeutically effective amount of a disease-modifying antibody therapy to said patient, wherein said patient has at least one phase rim lesion (PRL) in at least one susceptibility-weighted magnetic resonance image (MRI), or the patient has at least one slowly expanding lesion (SEL) in at least one T1-weighted/T2-weighted MRI (see claim 1). The ‘721 application is drawn to a method of reducing and/or treating chronic active white matter lesions in an early-stage and/or asymptomatic MS patient comprising administering a therapeutically effective amount of a disease-modifying antibody therapy to said patient, wherein said patient has at least one PRL in at least one susceptibility-weighted MRI, or the patient has at least one SEL in at least one T1- weighted/T2-weighted MRI (see claim 2). The ‘721 application is drawn to the method according to claim 9, wherein natalizumab is administered in a biphasic dosing regimen, wherein the biphasic regimen comprises an induction phase comprising administration of natalizumab once a month for about 10 to about 14 months, followed by a chronic phase comprising administration of natalizumab once every 5, 6, 7 or 8 weeks (see claim 10). The ‘721 application is drawn to the method according to claim 10, wherein at least one phase or both phases of the biphasic protocol comprises subcutaneous (SC) administration (see claims 11 and 12). The ‘721 application is drawn to a method for reducing and/or treating chronic lesion activity in an asymptomatic and/or early-stage MS patient (e.g. having no relapse events) comprising a) identifying at least one phase rim lesion (PRL) in at least one susceptibility-weighted magnetic resonance image from a patient known or suspected of having chronic lesion activity, b) identifying at least one slowly- expanding lesion (SEL) in at least one T1-weighted/T2-weighted MRI from said patient; c) determining if the at least one PRL co-localizes with the at least one SEL in said patient, and/or vice-versa, and d) in the event of co-localization initiating treatment with a disease-modifying antibody therapy (see claim 13). The ‘721 application is drawn to the method of any preceding claim, wherein the disease-modifying antibody therapy is natalizumab (see claims 9 and 16-17). The ‘721 application is drawn to the method according to any one of claims 13 to 15, wherein the disease-modifying antibody therapy is an anti-VLA-4 antibody, e.g. natalizumab or BIIB 107 (see claim 17). The ‘721 application is drawn to the method according to claim 17, wherein the anti-VLA-4 antibody is natalizumab, and the method further comprises administering to said patient a therapeutically effective amount of natalizumab in a biphasic dosing regimen, wherein the biphasic regimen comprises an induction phase comprising administration of the anti-VLA-4 antibody once every 2 weeks, once every 4 weeks, once every 30 days, or once a month for at least 6 months, for at least8 months, for at least 10 months, or for at least 12 months, followed by a chronic phase comprising administration of natalizumab once every 5 to 10 weeks (see claim 18). Lastly, the ‘271 application is drawn to the method according to claim 18, wherein the chronic phase comprises administration of natalizumab once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks (see claim 19).
As such, the ‘271 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-14 are not allowed.
Claims 1-4, 10-11, and 14 are rejected.
Claims 5-9 and 12-13 are objected to.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Clerico et al (Neurotherapeutics (2020) 17:200–207; published online: 08/26/2019) evaluated the noninferiority of the efficacy of an EID compared with the SID of natalizumab; in conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting (see Abstract).
Yamout et al (Multiple Sclerosis and Related Disorders, Volume 24, 2018, Pages 113-116) found that in patients treated with natalizumab, shifting from SID to EID has no negative effect on efficacy as evidenced by relapse rate, disability progression and MRI activity (see Abstract).
Ryerson et al (Journal of Neurology, Neurosurgery & Psychiatry 2018;89:A29; Abstract only) teach that in JCV Ab+ patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID.
Foley et al (Multiple Sclerosis and Related Disorders 31 (2019) 65–71) disclose that EID of natalizumab reduces nadir serum drug levels and α4-integrin receptor occupancy, as well as increases α4-integrin cell surface expression; the resulting increase in the number of open α4-integrin receptors may enhance immune surveillance of JCV and prevention of PML (see Abstract).
Wagner et al (Multiple Sclerosis Journal 2019; 25: (S2) 806–889: EP1585) disclose that efficacy did not differ significantly between SID and EID natalizumab treatment; their findings support EID as a treatment option, especially in an aging MS-population and after long-term treatment with natalizumab (see pages 880 and 881).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached at (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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