DETAILED ACTION
Claims 43, 45, 47-50, 53, 58, 63-64, and 66-72 are pending.
Status of Claims
The declaration under 1.131 filed on 06/02/2025 is noted. However, it was insufficient to
overcome the rejection of record under 35 USC 112(a) for new matter.
Claims 43, 45, 47-50, 53, 58, 63-64, and 66-72 are pending. Claims 45, 49-50, 53, 58,
64, 66, 68, 70, and 72 have been withdrawn.
Claims 43, 47-48, 63, 67, 69, and 71 are under examination.
Priority
The instant application filed 4/26/2018, is incorrectly identified as a continuation of parent application 14/377,454 on the filing receipt of 9/21/2018.
Applicant states that this application is a continuation application of the prior -filed application. A continuation application cannot include new matter. Applicant is required to delete the benefit claim or change the relationship (divisional application) to continuation-in-part because this application contains the following matter not disclosed in the prior-filed application: The disclosure of the prior-filed applications, fail 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 all claims of this application, as Applicant, added matter to the disclosure which is not supported by the disclosure of the parent application as originally filed specifically the limitations as explained in the new matter rejection above.
Because this application names the inventor or at least one joint inventor named in the prior application, it may constitute a continuation-in-part of the prior application. Should applicant desire to claim the benefit of the filing date of the prior application, attention is directed to 35 U.S.C. 120, 37 CFR 1.78, and MPEP § 211 et seq. 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 instant examined claims 43, 47-48, 63, 67, 69 ,71 are given priority only to the filing date of 4/26/2018.
Response to Arguments
On pp.7- 8 applicant argues that the pending claims do not encompass new matter, and the current application is properly designated as a continuation of the parent application, U.S.
application number 14/377,454 with a priority date of 02/07/2012, the filing date of the parent
Great Britain application. However, as discussed in the 35 USC 112(a) New Matter rejection below, the claims in the instant application raise new matter issues and thus do not qualify for the Great Britain filing date of 02/07/2012.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 43, 47-48, 63, 67, 69, and 71 are rejected under 35 U.S.C. §112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art (hereafter the Artisan), that the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR §1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application".
Claim 43 has been amended to recite A method of treating a human subject determined to have secondary progressive multiple sclerosis (
SPMS), said method comprising: (A) obtaining the results of an in vitro method for diagnosing multiple sclerosis (MS), wherein the method comprises:(i) obtaining a blood sample from a human test subject, and a blood sample from an individual with relapsing remitting multiple sclerosis (RRMS); (ii) detecting a change in relative concentrations of two or more metabolites in the sample [..] wherein the blood metabolites comprise: a) wherein the change detected is a decrease in the concentration of at least fatty acid in the blood sample from the test subject relative to the blood sample from the individual with RRMS; or (b) phosphocholine, and wherein the change detected is a decrease in the concentration of
at least phosphocholine test subject relative to the blood sample from the individual with RRMS; wherein said concentration changes are indicative of the presence of SPMS, thereby determining that the subject has SPMS; and
(B) administering a therapy for; SPMS to the human test subject determined to have SP phase MS SPMS; or (b) RRMS to the human test subject determined not to have SPMS, wherein the therapy for SP MS is a neuroprotective therapy (claim 43), wherein the human test subject determined to have SPMS is administered a therapy for SP MS instead of a therapy for RR MS (claim 63), wherein the therapy for RRMS is an anti-inflammatory therapy (claim 67) wherein the test subject has yet to manifest the outward clinical signs of SPMS.(claim 69).
Applicant argues that no new matter is introduced by the amendments, however,
the instant specification appears devoid of such description comprising a step of (B)
administering a therapy for; SP phase MS SPMS to the human test subject determined
to have SP phase MS SPMS; or (b) RRMS to the human test subject determined not to
have SPMS wherein the therapy for SPMS is a neuroprotective therapy (claim 43), wherein the
human test subject determined to have SPMS is administered a therapy for SP MS instead of a therapy for RR MS (claim 63), wherein the therapy for RRMS is an anti-inflammatory therapy
(claim 67).
While the specification generally discloses new treatments are required in progressive diseases and generally mentions identifying differences in MS phenotypes may identify key mechanisms as the first step for developing new strategies to prevent disability (page 1 lines 20-24) and that the method provides new biomarkers for evaluating neuroprotective treatment (page 7 first paragraph) and enables medical professionals to make improved choices regarding therapy options for an MS patient sooner, (page 12 first paragraph), the instant specification appears devoid of such description of an active step of administering specific agents to a specific subject population as recited i.e. administering a therapy for; SPMS to the human test subject determined to have SP phase MS SPMS; or (b) RRMS to the human test subject determined not to have SPMS wherein the therapy for SPMS is a neuroprotective therapy (claim 43), wherein the human test subject determined to have SPMS is administered a therapy for SP MS instead of a therapy for RR MS (claim 63), wherein the therapy for RRMS is an anti-inflammatory therapy (claim 67). In addition, the specification is void of any disclosure regarding any active step of administering a therapy as claimed wherein the human subject has yet to manifest the outward clinical signs of SPMS as claimed. Furthermore, regarding amended claim 63, the specification is devoid of any teachings regarding obtaining a blood sample from a
subject with RRMS that is treated, wherein a metabolic change is indicative of SP MS regardless of any metabolomic effect of a therapeutic agent.
While there is no in haec verba requirement, newly added claims or claim limitations
must be supported in the specification through express, implicit, or inherent disclosure. In this
case, as previously explained, neither the original claims or the original spec/drawings provide
EXPLICIT SUPPORT. The term "implicit disclosure" relates solely to matter which is not
explicitly mentioned, but is a clear and unambiguous consequence of what is explicitly
mentioned BUT NOT merely obvious (see Lockwood Airlines CAFC case).
In this case, although, it might be “obvious” to obtain a blood sample from a human test subjects and detect a change in the relative concentration of two or more metabolites relative to metabolites from an individual with RRMS, wherein the change is indicative of SPMS and administer differential treatment i.e. a therapy for SPMS or RRMS wherein the human test subject determined to have SPMS is administered a therapy for SP MS instead of a therapy for RR MS (claim 63), wherein the therapy for RRMS is an anti -inflammatory therapy (claim 67). After practicing applicant’s disclosed/claimed assays; there is no express or implicit teaching in the specification indicating possession to do so.
The specification fails to disclose either explicitly or implicitly, the newly introduced
limitations, as claimed. MPEP 2163.06 notes: "If new matter is added to the claims, the
examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description
requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981)." MPEP 2163.02
teaches that "Whenever the issue arises, the fundamental factual inquiry is whether a claim
defines an invention that is clearly conveyed to those skilled in the art at the time the application
was filed. If a claim is amended to include subject matter, limitations, or terminology not present
in the application as filed, involving a departure from, addition to, or deletion from the disclosure
of the application as filed, the examiner should conclude that the claimed subject matter is not
described in that application.
This is a new matter rejection.
Response to Arguments
Applicant's arguments filed 01/14/2026 have been fully considered but they are not
persuasive.
On pp. 10-12 applicant argues that it is clear in the background section that the methods disclosed are to improve on clinical methods known at the time of the instant application to initially diagnose and to distinguish RR MS from SP MS. Applicant directs the Office to the specification teaching that variations in metabolite concentrations can be associated with specific MS diseases phases (see specification page 11). Applicant argues that the specification not teaching obtaining a blood sample from a subject with RR MS that is treated, wherein a metabolic change is indicative of SP MS regardless of any metabolic effects of a therapeutic treatment does not change the fact that the applicant discloses a method for distinguishing a patient with RR MS from one with SP MS.
However, the method of the instant application is a method of treating a human subject determined to have secondary progressive multiple sclerosis (SP MS). The examiner understands that determining if the patient has RR MS or SP MS is a step of the claimed method, but the other limitations of the claim still need to be considered. The new matter rejection is directed towards the treatment limitations of the claims. The specification (filed on 04/12/2021) only broadly recites treatment methods, as “anti-inflammatory therapies” is recited once in the specification, on page 2, but the specification does not point out any specific anti- inflammatory therapies that can be used with RRMS. The specification does not provide any specific examples of “neuroprotective therapies”. In fact, the specification does not recite that a treatment for SP MS is neuroprotective therapies and is silent towards anti-inflammatory therapies being used in a subject who has RRMS.
Applicant is reminded that when pointing out support, the support needs to be in reference to the originally filed specification.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 43, 47-48, 63, 67, 69 ,71 are rejected under 35 U.S.C. 103 as obvious
over Anthony et al., (US 2015/0338389) in view of Ciotti et al., (Ciotti, John Robert, and Anne
Haney Cross. “Disease-Modifying Treatment in Progressive Multiple Sclerosis.” Current
treatment options in neurology vol. 20,5 12. 7 Apr. 2018, doi:10.1007/s11940-018-0496-3).
Regarding claim 43, Anthony teaches a method for determining secondary progressive multiple sclerosis (SP MS) in a human subjects, comprising
(A) obtaining the results of an in vitro method for diagnosing multiple sclerosis (MS),
wherein the method comprises:
(i) obtaining a blood sample from a human test subject, and a blood sample from an individual with relapsing remitting multiple sclerosis (RRMS) (see example 5; [0279] “Samples
from three cohorts of MS patients as well as age- and sex-matched control volunteers were
obtained with ethical approval (UK NHS C03.054, Metabolic profiling of urine in MS and
08/H0604/155): Set A: urine n=22, 30 and 28, serum n=15, 38 and 10; Set B: serum n=6, 10
and 7; Set C: serum n=5, 10 and 7 in RRMS, SPMS and control volunteers respectively. ”,
[0286] “We began with analysis of serum samples from MS patients in Set A. A model built
using the CPMG spectra and separating all MS patients from the control cohort was predictive
(q2=0.41). Furthermore, the comparisons between individual MS patient and control groups
were significant (q2=0.70, 0.61 and 0.42 for control vs. PPMS, RRMS and SPMS respectively;
Figure B1A and C).”).
ii) detecting a change in relative concentrations of two or more metabolites in the sample
with high resolution 1H-Nuclear Magnetic Resonance spectroscopy (NMR) (see [0280]
“Samples were defrosted at 4° C. prior to NMR. Blood samples were further centrifuged
(100,000×g, 30 min, 4° C.). Urine and plasma (100 μl EAE or 150 μl MS) were diluted in a 5 mm
NMR tube to a final volume of 600 μL with 0.24M sodium phosphate buffer (pH 7.4, 0.1% NaN3,
0.8% NaCl) in D2O containing 1 mM TSP (3-trimethylsilyl-1-[2,2,3,3,-2H4]propionate) as an
internal standard. 1H NMR spectra were acquired from each sample using a 16.4T NMR (700
MHz 1H) system (Bruker Avance III equipped with a 1H TCI cryoprobe). ”),
wherein the blood metabolites comprise fatty acids (see [0019] “Ᵹ 0.88,1.3,5.53”, [) or
phosphocholine (Ᵹ3.23) (see [0269] “Key metabolites from the original models separating Cr-
EAE animals from the control groups (CFA or naïve) were also identified. The metabolites that
showed greatest variation in these models were: fatty acid (δx-y 0.88, 1.58, 2.03), citrate (δx-y
2.5, 2.65), lactate (δx-y 1.32, 4.11), glucose (δx-y 3.25) and phosphocholine (δx-y 3.23).”);
wherein said concentration changes are indicative of the presence of SP MS, thereby
determining that the subject has SP MS (see [0026] “The present inventors have discovered
that differences in the concentrations of the above metabolites, as compared to a specific reference standard, are present in blood and/or urine of subjects having MS (and in particular,
MS of a specific disease phase), and that determining the concentrations of said metabolites in
blood/urine from a test subject can be used to diagnose MS. Thus, the method of the present
invention can be used to diagnose MS and to differentiate between disease phases of MS. In
one embodiment, the method of the invention permits diagnosis of a specific disease phase of
MS.”, [0055] “The present inventors have discovered that variations in metabolite
concentrations (as described above) can also be associated with specific MS disease phases
(such as SP MS, RR MS, and PP MS). Thus, the present inventors have discovered that it is
possible to diagnose a specific MS disease phase in a test subject. This can be achieved both
in subjects who have not previously been diagnosed with MS and in subjects who have
previously been diagnosed with MS.”).
Anthony is does not teach (B) administering a therapy for: (a) SP MS to the human
subject determined to have SP MS; or (b) RR MS to the human test subject determined not to
have SP MS; wherein the therapy for SP MS is a neuroprotective therapy.
Ciotti teaches (B) administering a therapy for: (a) SP MS to the human subject
determined to have SP MS; wherein the therapy for SP MS is a neuroprotective therapy (see
table 1 on page 8 and 14 “Neuroprotection/immunomodulation/remyelination”, page 20 “A
phase 2 trial of domperidone in SPMS patients is underway (NCT02308137). Results from MS-
SMART, a phase 2b trial repurposing three medications with potential neuroprotective effects
(amiloride, fluoxetine, and riluzole) in SPMS patients, are pending (NCT01910259).”).
It would have been prima facie obvious, at the time of the instant application, to further
treat the differentially diagnosed MS SPMS and RRMA human subjects of Anthony et al., with
differential treatments. i.e., a therapy for SPMS that includes a neuroprotective therapy to
improve patient outcome. One would be motivated to have used neuroprotective therapy for
patients with SPMS because as Ciotti teaches, the patients treated with neuroprotective therapy had disability improvement (The Expanded Disability Status Scale (EDSS) decreased) (see table 1).
Regarding claim 47, Anthony teaches wherein the concentrations of the metabolites
are determined using NMR spectroscopy (see [0280] “Samples were defrosted at 4° C. prior to
NMR. Blood samples were further centrifuged (100,000×g, 30 min, 4° C.). Urine and plasma
(100 μl EAE or 150 μl MS) were diluted in a 5 mm NMR tube to a final volume of 600 μL with
0.24M sodium phosphate buffer (pH 7.4, 0.1% NaN3, 0.8% NaCl) in D2O containing 1 mM TSP
(3-trimethylsilyl-1-[2,2,3,3,-2H4]propionate) as an internal standard. 1H NMR spectra were
acquired from each sample using a 16.4T NMR (700 MHz 1H) system (Bruker Avance III
equipped with a 1H TCI cryoprobe).”).
Regarding claim 48, Anthony teaches recording the output of at least one step on a
data-storage medium (see [0195] “In one embodiment, the method of the invention further
comprises recording the output of at least one step on a data-storage medium”).
Regarding claim 63, it would have been prima facie obvious, at the time of the instant
application, to not use the RRMS treatment protocol for a subject diagnosed with SP MS in
order to improve patient outcome, improve effectiveness, and minimize unnecessary side
effects.
Regarding claim 67, Ciotti teaches the therapy for RR MS is an anti-inflammatory
therapy (see table 1 on page 4 “Immunosuppressants/anti-inflammatory medications”).
It would have been prima facie obvious, at the time of the instant application, to further
treat the differentially diagnosed MS SPMS and RRMA human subjects of Anthony et al., with
differential treatments. i.e., a therapy for RRMS that includes anti-inflammatory therapy to
improve patient outcome. One would be motivated to use anti-inflammatory therapy in patients
with RR MS patients as Ciotti teaches, MS is an immune-mediated disorder and a much greater proportion of active, inflammatory MS plaques is found in RRMS (see page 12). Ciotti further provides motivation by teaching that anti-inflammatory therapies are already approved
treatments for RRMS, such as dimethyl fumarate (see page 19).
Regarding claim 69, Anthony teaches wherein the test subject has yet to manifest the
outward clinical signs of SP MS (see [0056] “the method of the present invention permits
diagnosis of a disease phase of MS in the absence of outward clinical signs of said phenotype.
Thus, by way of further example, the method of the present invention allows the early diagnosis
of secondary progressive phase MS in a patient previously diagnosed with relapsing remitting
phase MS, where the patient has yet to manifest the outward clinical signs of secondary
progressive MS.”).
Regarding claim 71, Anthony teaches wherein the blood metabolites comprise fatty
acid and phosphocholine (see [0019] “Ᵹ 0.88,1.3,5.53”, [0269] “Key metabolites from the
original models separating Cr-EAE animals from the control groups (CFA or naïve) were also
identified. The metabolites that showed greatest variation in these models were: fatty acid (δx-y
0.88, 1.58, 2.03), citrate (δx-y 2.5, 2.65), lactate (δx-y 1.32, 4.11), glucose (δx-y 3.25) and phosphocholine (δx-y 3.23).”).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to consider combining Anthony’s methods of diagnosing multiple sclerosis (MS) with Ciotti’s methods of differential treatments for MS to improve patient outcome. Anthony teaches that inflammation predominates during the relapsing phase whereas neurodegeneration is the pathological substrate of disability during the progressive phase although there is much overlap and because therapies that can treat the inflammatory relapsing phase i.e., interferons and therapies that can reduce the disability during the progression phase i.e., immunosuppressants/anti-inflammatory medications such as Mitoxantrone (table 1) as taught by Ciotti and neuroprotection/immunomodulation/remyelination medications such as Ibudilast (table 1) as taught by Ciotti. Ciotti provides motivation by teaching that MS is an immune-mediated disorder and a much greater proportion of active, inflammatory MS plaques is found in RRMS (see page 12). Ciotti provides further motivation by teaching that the patients treated with neuroprotective therapy had disability improvement (The Expanded Disability Status Scale
(EDSS) decreased). Lastly, Ciotti teaches that neuroprotection/immunomodulation/remyelination and immunosuppressant/anti-inflammatory
therapy methods have already been approved treatments for various MS subtypes. One of
ordinary skill in the art would have been motivated to combine the teachings of Anthony and
Ciotti as they both teach MS treatment methods. The artisan would have had reasonable expectation of success based on the cumulative disclosures of these prior art references.
Response to Arguments
Applicant's arguments filed 01/14/2026 have been fully considered but they are not
persuasive.
On p. 12-13 applicant argues that Anthony is not citable as prior art to the instant
application because the instant application does not contain new matter. The arguments
pertaining to new matter can be found in the 35 USC 112(a) new matter rejection above.
No other arguments pertaining to the prior art reference Anthony et al., has been recited.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MCKENZIE A DUNN whose telephone number is (571)270-0490. The examiner can normally be reached Monday-Tuesday 730 am -530pm, Wednesday-Friday 730 am-430 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571)272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678