DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2021/067769, filed 06/29/2021. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. GB2103184.4, filed on 03/08/2021 in the United Kingdom and to Application No. GB2009864.6. filed on 06/29/2020 in the United Kingdom.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed on 8/10/2023, and the information disclosure statement filed on 9/20/2023 are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
In page 3 line 25, “an value” appears to be a typographical error, namely it is suggested that “an value” read as “a value”.
In page 4 line 9, “reference group can a group” appears to be a typographical error, namely it is suggested that “reference group can a group” read as “reference group can be a group” (emphasis added).
Appropriate correction is required.
Claim Objections
Claims are objected to because of the following informalities:
In claim 22 line 6, “to reference value” appears to be a typographical error, namely it is suggested that “to reference value” read as “to a reference value” as per claim 11.
In claim 25 line 2, Applicant uses the abbreviation “MRC”; it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is used in order to improve clarity and avoid confusion.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The claims recite “…obtaining a sample from a patient suffering from CIDP; determining the concentration of serum neurofilament light chain (sNfL) in the sample…”
The limitation "the concentration" in line 4 of claim 10 and line 5 of claim 22 is not clear because there is insufficient antecedent basis for this limitation in the claim. It is not clear to what concentration is being referred to because a concentration of sNfL is not previously recited.
Claims 11-21 and 23-26 are included because they depend from rejected claims 10 or 22, but fail to clarify the scope of patent protection sought.
Claim 14 recites “..based on the difference in the concentration of sNfL…”. The limitation “the difference” in line 2 is not clear because there is insufficient antecedent basis for this limitation in the claim. It is not clear to what difference is being referred to because a difference in the concentration of sNfL is not previously recited.
Claims 16-17 recite “…wherein the baseline treatment…”. The limitation “the baseline treatment” in line 1 is not clear because there is insufficient antecedent basis for this limitation in the claim. It is not clear to what baseline treatment is being referred to because a baseline treatment is not previously recited. Furthermore, claim 16 recites “wherein the baseline treatment has been administered for at least two years”. The limitation “has been administered for at least two years” is not clear because it suggests two years of baseline treatment extending into a present moment in time, but no time is recited. It is not clear when in the method the baseline treatment of at least two years is claimed. A person having ordinary skill in the art would question what is encompassed by the claim.
Furthermore, claim 17 recites “the administration of intravenous immunoglobulins, plasma exchange, the administration of a combination of intravenous immunoglobulins and steroids, and the intravenous administration of immunoglobulins and azathioprine”. However, these limitations seem to lack antecedent basis because they are drawn to the baseline treatment, which lacks antecedent basis. A person having ordinary skill in the art would be confused by the limitations recited in claim 17.
Claim 18 recites “wherein administering a treatment comprises administering a more intensive treatment to the progressor and/or non-responder patient”.
However, it is not clear what “a more intensive treatment” refers to. The claim suggests a comparison to another treatment, but it is not clear what other treatment is used in the comparison. A more intensive treatment to what? The claim is considered vague and therefore is rejected under 112b.
Claim 19 recites “…a combination of intravenous immunoglobulins, plasma exchange, steroids, and/or immunosuppressive drugs”. However, it is not clear how “a combination” can have “and/or” because a combination would necessarily contain more than one. It appears that “or” limits the combination to not a combination, which is not clear. A person having ordinary skill in the art would question the metes and bounds of the claim.
Claim 21 recites “wherein the progressor and/or non-responder patient is immediately started on the more intensive treatment after diagnosis”. However, the term “immediately” is considered a relative term which renders the claim indefinite. The term “immediately” 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 limitation “immediately” could be interpreted as being instantaneously, i.e. at the same time, as well as within a relative time frame. Therefore, a person having ordinary skill in the art would question the scope of the claim. Also, it is not clear to what “diagnosis” the claim is referring because there is no previous step of diagnosing, i.e. this limitation seems to lack antecedent basis. A person having ordinary skill in the art would not readily recognize what “diagnosis” is being claimed.
Claim 22 recites “An improved method of identifying disease progression or therapy response in a patient with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the improvement comprising:…”.
Claim 22 is written in Jepson format (see MPEP 2129, III). However, the preamble fails to recite a clear and complete description of the prior art (the format described in 37 CFR 1.75(e);). Given that the preamble is incomplete, the claim is considered indefinite. A person having ordinary skill in the art would not recognize the metes and bounds of the claim.
Claims 23-26 are included in this rejection because they depend from rejected claim 22 but do not clarify the scope of patent protection sought.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 10-26 are rejected under 35 U.S.C. 101 because the claims are directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims recite “determining the concentration of serum neurofilament light chain (sNfL) in the sample” “to identify the patient as being a progressor and/or non-responder” (claim 10), “wherein the increased sNfL value is indicative of disease progression or a need to switch therapies” (claim 22).
The natural relationship to which the claims are directed (i.e., the relation between sNfL levels and disease progression or need to switch therapies/response to therapy) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of sNfL and the progression of disease or need to switch therapies/treatment response.
The correlation between sNfL levels and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility. Similarly, it is a naturally occurring phenomenon that sNfL levels are elevated to different extents in CIDP vs. in other diseases.
Additionally, the claims also recite steps of “comparing the determined concentration of sNfL to reference value; and identifying the patient as a progressor and/or non-responder when the concentration of sNfL is increased compared to the reference value” (claim 22). Claim 11 recites “wherein the concentration of sNfL in the sample is compared with a reference value, wherein: an increased value compared to the reference value is indicative of the patient being a progressor and/or non-responder; and/or a decreased value compared to the reference value is indicative of the patient responding to the treatment”
The claimed steps of identifying disease progression or a need to switch therapies/therapy response by comparing the determined sNfL concentration to a reference value may also be categorized as abstract ideas, namely mental processes/concepts performed in the human mind (such as a doctor simply thinking about the measured level of sNfL in relation to a cutoff value and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying disease progression or a need to switch therapies solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data (in this case, comparing a numerical level to a reference value) represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo (which also involved specific numerical cutoff levels).
Claims 12, 23 and 25 merely limit the sample and disease progression used in the natural correlation. Claims 14 and 26 merely limit the reference value used in the mental comparison. Therefore, these claims are further directed to at least one judicial exception.
Step 2A, Prong 2
The claims also recites “obtaining a sample from a patient suffering from CIDP” and “wherein the concentration of sNfL is determined via an immunoassay” (claims 13 and 24). Such steps of providing a sample and measuring the concentration of sNfL therein using an antibody are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of measuring sNfL are recited at a high level of generality and are not tied, for example, to any particular antibody, machine or apparatus.
Claim 10 further recites “administering a treatment to the progressor and/or non-responder patient, wherein the treatment comprises intravenous immunoglobulins, plasma exchange, steroids, immunosuppressive drugs, or a combination thereof”.
Claim 15 recites “wherein the patient is receiving a baseline treatment”.
Claim 16 recites “wherein the baseline treatment has been administered for at least 2 years”
Claim 17 recites “wherein the baseline treatment is selected from the group consisting of the administration of intravenous immunoglobulins, plasma exchange, the administration of a combination of intravenous immunoglobulins and steroids, and the intravenous administration of immunoglobulins and azathioprine”.
Claim 18 recites “wherein administering a treatment comprises administering a more intensive treatment to the progressor and/or non-responder patient”.
Claim 19 recites “wherein the more intensive treatment comprises a combination of intravenous immunoglobulins, plasma exchange, steroids, and/or immunosuppressive drugs”.
Claim 20 recites “wherein the patient is receiving a baseline treatment and the treatment is changed to the more intensive treatment when the patient is identified as a progressor and/or non-responder”.
Claim 21 recites “wherein the progressor and/or non-responder patient is immediately started on the more intensive treatment after diagnosis”.
These “treating” steps of claims 10 and 15-21 are insufficient to integrate the judicial exceptions as they are not limited to a particular treatment.
The recited steps of “administering… intravenous immunoglobulins, plasma exchange, steroids, immunosuppressive drugs, or a combination thereof” are recited at a high level of generality and are not limited to a particular treatment. Such highly generalized treatment limitations – which do not require any specific treatment for CIDP – do not amount to sufficient practical application to provide patentability. Although a claim limitation can integrate a judicial exception by applying or using the judicial exception(s) to effect a particular treatment or prophylaxis for a disease or medical condition, in this case no specific or particular treatment is set forth.
The level of generality in the instant claims stands in contrast to the treatment claims found patent-eligible in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117 (Fed. Cir. 2018) and Natural Alternatives Int’l v. Creative Compounds LLC, 2017 WL 1216226 (Fed. Cir. Mar. 15, 2019). The claims at issue in Vanda recited administering a specific drug (iloperidone) at specific dosage ranges based on a patient’s genotype. Vanda, 887 F.3d at 1135. Accordingly, the court found that although the inventors recognized the relationships between iloperidone, a patient’s genotype, and QTc prolongation, what they claimed is “an application of that relationship,” i.e., “‘a new way of using an existing drug’ that is safer for patients because it reduces the risk of QTc prolongation.” Id. (quoting Mayo, 566 U.S. at 87). The Federal Circuit characterized the Vanda claims as being directed to “a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.” Id. at 1136. Similarly, the Federal Circuit found that the claims in Natural Alternatives “contain specific elements that clearly establish they are doing more than simply reciting a natural law,” such as specifying a patient population, particular results to be obtained, specific compounds to be administered to achieve the claimed results, and dosages via an “effective” limitation. Natural Alternatives, 4-5.
In contrast to the claims in Vanda and Natural Alternatives, the present claims do not specify a particular result to be obtained, a compound to be administered to achieve a claimed result, or any specific dosage of a specific compound.
The recited treating steps do not limit the claims to a particular application; instead, the effect of the treatment limitations “is simply to tell doctors to apply the law somehow when treating their patients.” Mayo, 566 U.S. at 81-82.
Here, the claimed treatment step is instead merely an instruction to “apply” the exception in a generic way. Thus, the treatment step does not integrate the abstract idea(s) into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of obtaining a sample and measuring the concentration of sNfL therein, do not add significantly more to the judicial exception(s). The step of measuring sNfL is recited at a high level of generality and is not limited, for example, to any specific testing technique.
In this case, it was well-understood, routine and conventional to determine the concentration of NGAL in samples using an immunoassay.
See for example, Lieverloo et al. J Pe11pher Nerv Syst. 2019;24:187-194. DOI: 10.1111/jns.1231- Cite No. 3 of IDS 8/10/2023 ("Lieverloo"). Lieverloo teaches obtaining a sample from a patient suffering from CIDP, wherein the sample is serum; determining the concentration of serum neurofilament light chain (sNfL) in the sample (“Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy” Title, “CIDP patients were studied” Abstract), wherein the concentration of sNfL is determined via an immunoassay (“sNfL levels were measured at the Laboratory of University Hospital Basel by a Simoa assay using the capture monoclonal antibody (mAB) 47:3 and the biotinylated detector mAB 2:1 from UmanDiagnostics transferred onto the Simoa platform” page 189 col. 1 para. 1).
Also, Mariotto et al. J Peripher Nerv Syst. 2018;23:174-177. DOI: 10.1111/jns.12279-Cite No. 4 of IDS 8/10/2023 (“Mariotto”). Mariotto teaches “NFL analysis Paired CSF and serum samples were centrifuged at room temperature, aliquoted in polypropylene tubes within 1 hour of collection, and then stored at -80°C. The concentration of NFL protein was determined in duplicates by investigators blinded to clinical data using a H D-1 immunoassay analyzer, Quanterix, Simoa, Lexington, MA, USA, which runs ultra-sensitive paramagnetic bead-based enzyme-linked immunosorbent assays” (page 175 col. 2 para. 3).
Khalil et al. Nature Reviews, Neurology, Vol. 14, pages 577-589, October 2018-Cite No. 3 of IDS 9/20/2023 (“Khalil”) teaches that “the detection of neurofilaments bas improved...moving towards ever more clinically useful capabilities. First-generation immunoassays… Second-generation sandwich ELISA technology produced the first reliable quantitative data that enabled assessment of the prognostic and diagnostic value of NfH and NfL in the CSF in human disease… Third-generation ECL technology led to a substantial improvement… commercial SiMoA kits for the detection of NfL and phosphorylated NfH are available” (page 580 col. 1 paras. 2-4 and col. 2 para. 2).
In view of the above evidence, the claimed steps of determining the concentration of sNfL using an immunoassay do not add any feature that is more than well-understood, purely conventional, or routine in the field of diagnostics and biochemical assay methodologies.
Furthermore, there is nothing of record to suggest that the claims involve novel treatment steps. Treating is recited at a high level of generality. Appending a generic, routine, and obvious post-solution treatment step does not provide a sufficient inventive concept to satisfy § 101. As was the case in Mayo and Ariosa, the method claims at issue here amount to "nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients" using "conventional steps, specified at a high level of generality." Mayo, 132 S. Ct. at 1298, 1300; Ariosa, 788 F.3d at 1377-78
Furthermore, there is evidence that administering a treatment to the progressor and/or non-responder patient, wherein the treatment comprises intravenous immunoglobulins, plasma exchange, steroids, immunosuppressive drugs, or a combination thereof is well understood routine and conventional.
For example, Lieverloo teaches administering a treatment to the progressor and/or non-responder patient, wherein the treatment comprises intravenous immunoglobulins, plasma exchange, steroids, immunosuppressive drugs, or a combination thereof (“On group level, sNfL levels at follow-up assessment in patients with active disease were higher compared to patients with stable disease when corrected for age (Figure 3)…It should be emphasized that MT patients were followed closely during treatment withdrawal and [intravenous Immunoglobuline] IVlg was reinstituted within a week after establishing a relapse” page 193 col. 1 para. 3). Lieverloo further teaches that “[i]n the IT cohort (N = 29), patients were treated for 6 months with IVlg treatment (N = 7), corticosteroids, (N = 5) or a combination of IVlg and corticosteroids (N = 17)…The remission cohort (N = 27…had been treated with corticosteroids (N:11), IVlg (N: 6), a combination of treatments (N: 8))” (page 189 col. 2 para. 3 and page 190 col. 1 para. 1).
Also, Mariotto teaches “nine subjects received previous therapies (four with steroids, two with intravenous immunoglobulins, and three with multiple drugs)”.
Merkies et al. J Neural Neurosurg Psychiatry 2010;81 :1194-1199. doi:10.1136/jnnp.2009.194324-Cite No. 39 of IDS 8/10/2023 (“Merkies (2010)”) Merkies (2010) teaches that intravenous immunoglobulins are an established and effective treatment for CIDP (“Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance” Title).
Lehmann et al. J Neurol Neurosurg Psychiatry 2019;90:981-987. doi: 10.1136/jnnp-2019-320314-Cite No. 32 of IDS 8/10/2023 (“Lehmann”) teaches that “CIDP…responds to immunosuppressive therapies” (page 981 col. 1 para. 1). Lehmann further teaches that “[t]reatment of patients with CIDP is complex and requires individualized treatment strategies. First-line therapies that have been shown to be efficacious include corticosteroids, IVIg and plasma exchange” (page 984 col. 2 para. 4).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 10-13, 18-24 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lieverloo et al. J Pe11pher Nerv Syst. 2019;24:187-194. DOI: 10.1111/jns.1231- Cite No. 3 of IDS 8/10/2023 ("Lieverloo").
Regarding claims 10-12 and 22-23, although claims 10 and 22 are indefinite (see 112b rejection above), in the interest of compact prosecution, the claims are interpreted as reciting “a concentration”. Also, claim 22 is interpreted to be drawn to “a method” (not an improvement). Lieverloo teaches a method of treating Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), a method of identifying disease progression or therapy response in a patient with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the methods comprising: obtaining a sample from a patient suffering from CIDP, wherein the sample is serum; determining the concentration of serum neurofilament light chain (sNfL) in the sample (“Serum neurofilament light chain in chronic inflammatory demyelinating polyneuropathy” Title, “We hypothesized that serum neurofilament light chain (sNfL) reflects disease activity by detecting ongoing neuro-axonal damage in CIDP. Three prospective cohorts of CIDP patients were studied: (a) patients starting induction treatment (IT cohort, N = 29) measured at baseline and 6 months after starting treatment; (b) patients on maintenance treatment (MT) starting intravenous immunoglobuline (IVIg) withdrawal (MT cohort, N = 24) measured at baseline and 6 months after IVIg withdrawal or at time of relapse; and (c) patients in long-term remission without treatment (N = 27)” Abstract) to identify the patient as being a progressor and/or non-responder, comparing the determined concentration of sNfL to a reference value, wherein the concentration of sNfL in the sample is compared with a reference value, wherein: an increased value compared to the reference value is indicative of the patient being a progressor and/or non-responder; and/or a decreased value compared to the reference value is indicative of the patient responding to the treatment; and identifying the patient as a progressor and/or non-responder when the concentration of sNfL is increased compared to the reference value; wherein the increased sNfL value is indicative of disease progression or a need to switch therapies (“At follow-up assessment, patients with active disease (non-responders and patients who relapsed after IVIg withdrawal) had higher sNfL levels compared with patients with stable disease (responders and patients who were successfully withdrawn from IVIg treatment)” Abstract); and administering a treatment to the progressor and/or non-responder patient, wherein the treatment comprises intravenous immunoglobulins, plasma exchange, steroids, immunosuppressive drugs, or a combination thereof (“On group level, sNfL levels at follow-up assessment in patients with active disease were higher compared to patients with stable disease when corrected for age (Figure 3)…It should be emphasized that MT patients were followed closely during treatment withdrawal and [intravenous Immunoglobuline] IVlg was reinstituted within a week after establishing a relapse” page 193 col. 1 para. 3).
Regarding claims 13 and 24, Lieverloo teaches wherein the concentration of sNfL is determined via an immunoassay (“sNfL levels were measured at the Laboratory of University Hospital Basel by a Simoa assay using the capture monoclonal antibody (mAB) 47:3 and the biotinylated detector mAB 2:1 from UmanDiagnostics transferred onto the Simoa platform” page 189 col. 1 para. 1).
Regarding claim 18, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, “a more intensive treatment” is interpreted as a more intensive treatment than a baseline treatment. Lieverloo teaches wherein administering a treatment comprises administering a more intensive treatment to the progressor and/or non-responder patient (“It should be emphasized that MT patients were followed closely during treatment withdrawal and [intravenous Immunoglobuline] IVlg was reinstituted within a week after establishing a relapse” page 193 col. 1 para. 3). Note that although Lieverloo fails to use the language “a more intensive treatment”, the teaching of reinstituting intravenous immunoglobulins on patients that were on treatment withdrawal inherently provides the administration of a more intensive treatment than the baseline intravenous immunoglobulins being administered.
Regarding claim 19, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted as requiring one of a more intensive intravenous immunoglobulins, plasma exchange, steroids, or immunosuppressive drugs.
Lieverloo teaches wherein the more intensive treatment comprises intravenous immunoglobulins (page 193 col. 1 para. 3).
Regarding claim 20, Lieverloo teaches wherein the patient is receiving a baseline treatment and the treatment is changed to the more intensive treatment when the patient is identified as a progressor and/or non-responder (page 193 col. 1 para. 3).
Regarding claim 21, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the diagnosis is interpreted as referring to the identifying limitation of claim 10 line 4. Also, the limitation “immediately” is interpreted as limited to “within a week”. Lieverloo teaches wherein the progressor and/or non-responder patient is immediately started on the more intensive treatment after diagnosis (“within a week after establishing a relapse” page 193 col. 1 para. 3).
Regarding claim 26, wherein the reference value is a median concentration of sNfL in individuals without disease progression (“Horizontal bars show group medians” Figure 3 page 191).
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 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lieverloo as applied to claim 10 above, and further in view of Mariotto as evidenced by Merkies et al. J Neural Neurosurg Psychiatry 2010;81 :1194-1199. doi:10.1136/jnnp.2009.194324-Cite No. 39 of IDS 8/10/2023 (“Merkies (2010)”).
Regarding claim 14, Lieverloo teaches the method of claim 10 as discussed above.
Lieverloo further teaches wherein the patient is identified as a progressor and/or non-responder based on the difference in the concentration of sNfL over a time period of six months (Abstract). Lieverloo further teaches that “[c]urrently, axonal damage in CIDP can be assessed with nerve conduction studies (NCS) or needle electromyography. Better tools are needed because these techniques cannot discern ongoing axonal damage from residual axonal damage and because changes in the degree of axonal damage during treatment are difficult to quantify.4” (page 187 col. 2 para. 1).
Lieverloo fails to teach wherein the patient is identified as a progressor and/or non-responder based on the difference in the concentration of sNfL over a time period of one year.
Mariotto suggests a method of identifying CIDP progression (“Our aim was to determine the possible diagnostic and prognostic value of serum and cerebrospinal fluid (CSF) NFL levels in subjects with different forms of acquired peripheral neuropathies (PN)… chronic inflammatory demyelinating polyneuropathy (CIDP) and variants (N = 12)” Abstract), the method comprising: obtaining a sample from a patient suffering from CIDP; determining the concentration of serum neurofilament light chain (sNfL) in the sample (“Paired serum and CSF samples of 25 patients with acquired PN were analysed for NFL using an ultrasensitive technique (Quanterix, Simoa, Lexington, MA, USA)” Abstract); comparing the determined concentration of sNfL to reference value (“and compared with a group of 25 age-matched healthy subjects” Abstract); and identifying the patient as a progressor of CIDP when the concentration of sNfL is increased compared to the reference value; wherein the increased sNfL value is indicative of disease progression or a need to switch therapies (“A statistically significant correlation was observed between serum and CSF levels in cases with blood-nerve-barrier damage (r = 0.71, P < 0.01), and between serum NFL levels and disease activity at sampling (r = 0.52, P < 0.01) and at last follow-up (r = 0.53, P < 0.01) in all subjects” Abstract). Mariotto further suggests wherein the patient is identified as a progressor and/or non-responder based on the difference in the concentration of sNfL over a time period of one year (“Follow-up, median (range), mo…Chronic neuropathies, median (range),…78 (2-228)” Table 1, page 175 col. 1). With regards to the claimed period of one year, the prior art teaches a range of 2-228 months (0.16-19 years). In such a case, since there is a substantial overlap of the claimed range and the prior art, a prima facie case of obviousness exists because it would have been obvious to a person having ordinary skill in the art to arrive at the claimed period by selecting within the prior art range. See MPEP 2144.05. Mariotto further suggests that using a time period of one year enabled the identification of neuroinflammation-mediated axonal injury (“In conclusion, we present initial data suggesting that serum NFL levels might reflect neuroinflammation-mediated axonal injury in acquired PN” page 177 col. 1 para. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Lieverloo to rely on the period of one year taught by Mariotto because Mariotto suggests this timeframe also enables the diagnosis of axonal injury. One would have been motivated to make such a modification because Lieverloo teaches that there is a need for better diagnostics of axonal injury. A person having ordinary skill in the art would have had a reasonable expectation of success because both Lieverloo and Mariotto teach methods related to measuring sNfL in samples of CIDP patients and comparing the measured concentration to a reference value.
Regarding claim 15, Lieverloo in view of Mariotto teach the method of claim 14 as discussed above.
Lieverloo further teaches wherein the patient is receiving a baseline treatment (Abstract).
Regarding claim 16, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, “the baseline treatment” is interpreted as referring to a baseline treatment administered to the patient for at least two years from the sampling. Lieverloo in view of Mariotto teach the method of claim 14 as discussed above.
Lieverloo further teaches wherein the baseline treatment has been administered for at least 6 months (“MT cohort: CIDP patients who are stable on maintenance intravenous
immunoglobuline (IVlg) treatment for at least 6 months, starting IVlg withdrawal by lowering the original dose in steps of 25% following each infusion (N = 24)” page 188 col. 1 para. 7).
Lieverloo fails to teach wherein the baseline treatment has been administered for at least two years.
Mariotto suggests wherein the baseline treatment has been administered for at least two years (“The median time interval between the initial symptoms and sampling was 12 months (range: 0-168), and nine subjects received previous therapies (four with steroids, two with intravenous immunoglobulins, and three with multiple drugs)” page 175 col. 2 para. 5). Note that the specification discloses that a baseline treatment can also be considered “the treatment established closest to time of sampling” (page 8 lines 26-27). Therefore, given that Mariotto suggests that “nine subjects received previous therapies” at the time of sampling and that the follow-up happened 0.16-19 years after, the “previous therapies” of Mariotto closest to the time of sampling effectively address the baseline treatment claimed. Furthermore, although Mariotto fails to explicitly teach that the patients with CIDP were the ones who received the intravenous immunoglobulins, as evidenced by Merkies (2010), intravenous immunoglobulins are an established and effective treatment for CIDP (“Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance” Title), therefore, the teachings of CIDP and intravenous immunoglobulins by Mariotto inherently suggest to a person having ordinary skill in the art the treatment of intravenous immunoglobulins to the CIDP patients.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Lieverloo to rely on the baseline treatment being for 2 years instead of 0.5 years taught by Mariotto because it would have been a simple matter of applying a known technique to a known method. In this case, both Lieverloo and Mariotto teach a baseline treatment of at least half a year with intravenous immunoglobulins. Mariotto simply applies the art-recognized technique of having a baseline treatment of intravenous immunoglobulins for at least 2 years. Therefore a person having ordinary skill in the art would have found it obvious to apply the technique of Mariotto to the base method taught by both Lieverloo and Mariotto. A person having ordinary skill in the art would have had a reasonable expectation of success because both Lieverloo and Mariotto are drawn to measuring serum neurofilament light chain on patients receiving a baseline treatment of intravenous immunoglobulins.
Regarding claim 17, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, “the baseline treatment” is interpreted as referring to a baseline treatment administered to the patient selected from the group consisting of “an administration of intravenous immunoglobulins, plasma exchange, an administration of a combination of intravenous immunoglobulins and steroids, and an intravenous administration of immunoglobulins and azathioprine”. Lieverloo in view of Mariotto teach the method of claim 14 as discussed above.
Lieverloo further teaches wherein a baseline treatment selected from the group consisting of an administration of intravenous immunoglobulins (Abstract).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Lieverloo as applied to claim 22 above, and further in view of van Schaik et al. the Lancet Neurology Volume 17, Issue 1 p35-46 January 2018 http://dx.doi.org/10.1016/ S1474-4422(17)30378-2 -Cite No. 7 of IDS 8/10/2023.
Regarding claim 25, Lieverloo teaches the method according to claim 22 as discussed above.
Lieverloo further teaches assessing disease progression using “the Medical Research Council-sum score” on a 60-point scale (“Disability and impairment were assessed using…the Medical Research Council-sum score (MRC-SS, highest score of 60 indicating normal muscle strength)” page 188 col. 2 para. 1).
Lieverloo fails to teach an 80-point MRC sum score scale and is silent regarding disease progression being at least a 4 point decrease.
Van Schaik teaches that “[b]etween March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible… This trial is registered with ClinicalTrials.gov, number NCT01545076”… the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP” (Abstract). Van Schaik further suggests identifying a patient as a disease progressor wherein disease progression is a decrease of at least 4 points on an 80-point MRC sum score scale (“MRC sum score (possible range 0–80)” Table 1 , page 39 col. 2, “MRC (sum score)… Change from baseline –2·0 (–6·0 to 0·0)” Table 4 page 41). Note that although van Schaik fails to use the language “a decrease of at least 4 points”, the teaching that the range of the change in MRC sum score from baseline encompasses a value of “-6” inherently provides a decrease of at least 4 points. Van Schaik further teaches “Medical Research Council sum score (range 0–80; including shoulder abduction, elbow flexion, wrist extension, index finger abduction, hip flexion, knee extension, foot dorsiflexion, and great toe dorsiflexion)” (page 37 col. 2 para. 3). Van Schaik further teaches that “[t]he potential of relapse risk reduction with SCIg is similar to what has been observed in studies of IVIg” (page 44 col. 1 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Lieverloo to rely on the disease progression being a decrease in at least 4 points on an 80-point MRC sum score scale taught by van Schaik because van Schaik suggests that this enables the assessment of relapse risk reduction on CIDP patients and Lieverloo is concerned with disease progression or therapy response in CIDP patients. Furthermore, van Schaik teaches that an 80-point MRC sum score scale incorporates additional muscle groups in the calculation, thereby making the score more comprehensive. A person having ordinary skill in the art would have had a reasonable expectation of success because Schaik teaches that their study is registered with ClinicalTrials.gov, number NCT01545076; furthermore, van Schaik teaches that their results are “similar to what has been observed in studies of IVIg” and Lieverloo teaches studies of IVIg.
Conclusion
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/Fernando Ivich/Examiner, Art Unit 1678
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677