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