Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed May 28, 2026 is acknowledged. Claims 1-63, 69-70 and 75 are cancelled. Claims 64-68, 71, 73-74, 76, 79-83, 86-88, 90 and 93-94 are amended. Claim 102 is newly added. Claims 64-68, 71-74, 76-101 and new claim 102 are pending in this application. Election was made without traverse in the reply filed on November 24, 2025.
3. Claims 64-68, 71-74 and 76-102 are under examination in this office action.
4. Applicant’s arguments filed on May 28, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Priority
5. The priority for the claimed method recited in instant claims of the application is May 22, 2020.
The claimed method of treating MS comprising administering ofatumumab to a patient who has exhibited a decrease in a serum IgG level after receiving an earlier-modifying therapy other than ofatumumab wherein the decrease in the serum IgG level of the patient includes including below a concentration of 900mg/dL, 800mg/dL or 700mg/dL was only disclosed in EP20176057.6 filed on May 22, 2020 (seep. 4, line 13-p5, line 6; p. 6, lines 10-p. 7, line 24, claim 6 of EP20176057.6).
Response to Arguments
On p. 9-10 of the response, Applicant argues that the priority of the claimed method is April 9, 2020 because EP20169007.0 discussed treating MS and advantage of the claimed ofatumumab therapy including smaller reduction in immunoglobulin as compared to other diseases modifying therapies at p. 19, lines 31-36 and p.7, lines 17-28 and p. 18, lines 10-23.
Applicant’s arguments have been fully considered but they are not found persuasive. Contrary to Applicant’s arguments, the cited passages of EP20169007.0 do not provide support for the claimed method of treating multiple sclerosis in a patient who has exhibited a decrease in serum IgG level after receiving an earlier disease-modifying therapy other than ofatumumab, and wherein the decrease in the serum IgG level of the patient is below a concentration of 900mg/dL, 800mg/dL or 700mg/dL or below 80% of the baseline level at the start of the earlier disease-modifying therapy for the following reasons:
i. P. 19, lines 31-36 of EP20169007.0 only disclosed “ofatumumab had been expected to negatively affect the immune system, such immunoglobulins, which are necessary to acquire immunity after vaccination… rituximab, another anti-CD20 antibody, leads to a depression of IgM levels”, which is not “a decrease a serum IgG level including wherein the decrease in the serum IgG level of the patient includes including below a concentration of 900mg/dL, 800mg/dL or 700mg/dL”.
ii. P. 7, lines 17-28 of EP20169007.0 only disclosed “one of the most common adverse events associated with B-cell-depleting therapies such as ocrelizumab….be a reduction of Immunoglobulins (e.g. IgM)… ofatumumab therapy is advantageous compared to other B-cell-depleting therapies because it causes reduction of immunoglobulins (e.g. IgM) to a lesser extent……they may be vaccinated while on ofatumumab therapy…. they can be treated with ofatumumab despite previous or ongoing conditions other than multiple sclerosis”, which is not “a decrease a serum IgG level including wherein the decrease in the serum IgG level of the patient includes including below a concentration of 900mg/dL, 800mg/dL or 700mg/dL”.
iii. The claimed method of treating MS, comprising administering ofatumumab to a patient who has exhibited a decrease in serum IgG level including below a concentration of 900mg/dL, 800mg/dL or 700mg/dL after receiving an earlier disease-modifying therapy other than ofatumumab or the serum IgG level is below 80% of the baseline level at the start of the earlier-disease-modifying therapy was only disclosed in EP20176057.6 filed on May 22, 2020 (seep. 4, line 13-p5, line 6; p. 6, lines 10-p. 7, line 24, claim 6 of EP20176057.6).
Therefore, the priority for the claimed method in the instant application is May 22, 2020.
Specification
6. The objection to the specification is withdrawn in response to Applicant’s amendment to the specification.
Claim Rejections/Objections Withdrawn
7. The rejection of claims 64, 69-81, 86-88 and 93-101 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 69-70 and 75.
The rejection of claims 64-101 under 35 U.S.C. 103 as being unpatentable over Novartis-NCT02792231 (or COMB157G2302, Novartis Clinical trial protocol, published Aug 06, 2018) in view of Zoehner et al. (Ther. Adv. Neurol. Disord., 2019; 12:1-8), Hallberg et al. (Oral Presentations, Number 64, p. 20; Multiple Sclerosis J. 2019; 25: (S2) 3-130), Derfuss et al. (Oral Presentations, Number 65, p. 20; Multiple Sclerosis J. 2019; 25: (S2) 3-130) and Bar-Or et al. (Poster Number p6.1-008, the 72nd Annual Meeting of the American Academy of Neurology, April25-May 01, 2020; Toronto, ON, Canada) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 69-70 and 75.
The provisional rejection of claims 64-101 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 20-25, 28-32, 38, 42-44 and 47-93 of copending Application No. 17/753632, claims 1, 2, 4-7, 9, 18-21, 27, 31-37, 40-41 and 54-57 of copending Application No. 17/753,635, claims 26-45 of copending Application No. 18/286,030, or claims 16-36 copending Application No.18/683858 in view of Novartis-NCT02792231 (2018), Zoehner et al. (2019), Hallberg et al. (2019), Derfuss et al. (2019) and Bar-Or et al. (2020) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 69-70 and 75.
Claim Rejections/Objections Maintained
Claim Rejections - 35 USC § 112
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 82-85, 89-92 stand 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 pre-AIA the applicant regards as the invention. The rejection is maintained for the reasons of record and the reasons set forth above.
Response to Arguments
On p. 10-11 of the response, Applicant argues that the rejection has been overcome in view of amendment to the claims by reciting and defining a decrease relative to the level at the start of ofatumumab treatment.
Applicant’s arguments, see p. 10-11 of the response, filed 05/28/2026, with respect to the rejection(s) of claim(s) 64, 69-81, 86-88 and 93-101 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of amendment to claims 82-85 and 89-92.
Claims 82-85 and 89-92 are indefinite because:
i. Claims 82 and 89 recite the limitation "a LLN of …" in line 2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. The rest of claims are indefinite as depending from an indefinite claim.
Accordingly, the rejection of claim 82-85, 89-92 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is maintained.
New Grounds of Rejection Necessitated by the Amendment
The following rejections are new grounds of rejections necessitated by the amendment filed on May 28, 2026.
Claim Rejections - 35 USC § 112
9. 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 64-68, 72-74 and 76-102 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 64-68, 72-74 and 76-102 encompass using a genus of earlier disease-modifying therapy comprising a genus of anti-CD20 antibody that decreases the serum IgG level in patients after receiving the earlier disease-modifying therapy.
Applicant has not disclosed sufficient species for the broad genus of anti-CD20 antibody that decreases the serum IgG level in patients after receiving the earlier disease-modifying therapy.
The specification only describes patients treated with rituximab (RTX) or ocrelizumab (OCR) exhibited a decrease in serum IgG level after receiving rituximab (RTX) or ocrelizumab (OCR) (see p. 2-3 of the instant specification). However, the claims are not limited to treating patients who have exhibited a decrease in the serum IgG level after receiving rituximab (RTX) or ocrelizumab (OCR) set forth above. The specification fails to demonstrate that Applicant is in possession of a method of using any anti-CD20 antibody with no defined structure and capable of decreasing the serum IgG level in patients in the claimed method and treating the patients who have exhibited a decrease in the serum IgG level after receiving any anti-CD20 antibody with no defined structure.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, Applicant is in possession of treating patients who have exhibited a decrease in serum IgG level after receiving rituximab (RTX) or ocrelizumab (OCR). However, Applicant is not in possession of a method of treating patients who have been treated with other structurally and functionally undefined anti-CD20 antibodies and exhibited a decrease in serum IgG level after receiving the structurally and functionally undefined anti-CD20 antibodies.
As an initial matter, Applicant has provided no structures or sequences sufficiently detailed to show that he/she was in possession of the claimed invention as a whole. There was also no known or disclosed correlation between the required function (i.e. binding to CD20 and decreasing serum IgG in MS patients after receiving the treatment with the unknown defined anti-CD20 antibody) and any particular structure or sequence.
Applicant has not disclosed sufficient species for using the broad genus of anti-CD20 antibodies that decrease serum IgG levels in MS patients in the claimed method because the specification provides no well-established structurally and functionally relationship or correlation between the claimed genus of anti-CD20 antibody that decrease serum IgG levels in MS patients and specific anti-CD20 antibodies rituximab (RTX) or ocrelizumab (OCR).
In light of Amgen, Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describing a “fully characterized antigen” for an antibody is no longer adequate on its own to demonstrate possession of the antibody. Based on MPEP§2161.01 and 2163, the USPTO guidance regarding written description requirement of 35 U.S.C.§C112 (a), specifically concerning the written description requirement for claims drawn to antibodies and Federal Circuit decisions, when an antibody is claimed, 35USC112(a) requires adequate written description of the antibody itself. See Amgen 872 F.3d at 1378-79.
The court of the Federal Circuit also stressed that the “newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. See Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir.2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Furthermore, the Fed. Cir.’s decision in Amgen confirmed that post-filing disclosures may be informative in establishing the size of the claimed genus. In this case, there are numerous disclosures of novel antibodies that were published after applicants’ filing date and are not fairly described in it. The specification’s general reference to anti-CD20 antibodies “decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody” recited in independent claim 64 does not clearly suggest any particular sequences that can be used in order to result in the claimed anti-CD20 antibodies with the claimed features of decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody. As such, he cannot possibly have possessed the entire genus.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations 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. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum et al. (J. Mol. Biol.,1996; 262: 732-745) teaches that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see p. 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology, 2002; 169: 3076-3084) teaches that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.) and that although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site because although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.; Casset et al., BBRC, 2003; 307: 198-205). Vajdos et al. (J. Mol. Biol. 2002; 320: 415-428) also teaches that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Holm et al. (Mol. Immunol., 2007; 44: 1075-1084) teaches that although residues in the CDR3 of the heavy chain were involved in antigen binding, unexpectedly a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (J. Mol. Bio., 1999; 293: 865-881) teaches that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol., 1999; 294:151-162) teaches that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. These references demonstrate that in order to generate an antibody with the claimed binding activity or features, the antibody must comprise all 6 CDRs with defined sequences or structures in order to maintain the claimed antigen binding specificity and affinity. However, no such information is provided by the specification. Further, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
Applicant fails to teach what structures/amino acid sequences are for the claimed genus of anti-CD20 antibodies that “decrease serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody” recited in independent claim 64. Neither the specification nor the prior art provides sufficient descriptive information, such as definitive structural or functional features of the claimed genus of anti-CD20 antibodies decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody. There is no description of the conserved regions which are critical to the function of the claimed genus. There is no description of the sites at which variability may be tolerated and there is no information regarding the relation of the structure of other anti-CD20 antibodies containing structurally and functionally undefined sequences to the function of rituximab (RTX) or ocrelizumab (OCR). Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to isolate and identify what other anti-CD20 antibodies decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody might be. Since the common characteristics/features of other anti-CD20 antibodies decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of using the genus of anti-CD20 antibodies or treating patients who have exhibited a decrease in serum IgG levels after receiving the earlier disease-modifying therapy comprising the genus of anti-CD20 antibody.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-CD20 antibodies decreasing serum IgG levels in MS patients after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody, and therefore conception is not achieved until reduction to practice has occurred, 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 of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 and Centocor v. Abbott, 636 F.3d1341 (Fed. Cir. 2011) and AbbVie v. Janssen, 759 F.3d 1285 (Fed. Cir.2014). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Claim Rejections - 35 USC § 103
10. 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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 64-68, 71-74 and 76-102 are rejected under 35 U.S.C. 103 as being unpatentable over Novartis Clinical trial protocol-COMB157G2102 (Novartis- COMB157G2102 release date March 30, 2018, first publicly available as EudraCT Number: 2017-004702-17 on Aug 10, 2018; or NCT03560739, Novartis Clinical trial protocol, release date: March 30, 2018, first publicly available on June 06, 2018) in view of Ancau et al. (Exp. Opin. Biol. Ther. 2019; 19; 8: 829-843), Hallberg et al. (Oral Presentations, Number 64: Risk of hypogammaglobulinemia in long-term treatment with rituximab in multiple sclerosis, p. 20; Multiple Sclerosis J. 2019; 25: (S2) 3-130, cited previously) and Zoehner et al. (Ther. Adv. Neurol. Disord., 2019; 12:1-8. Doi:10.1177/17562864198878340, cited previously).
Claims 64-68, 71-74 and 76-102 as amended are drawn to a method of treating multiple sclerosis (MS), comprising administering ofatumumab to a patient who has exhibited a decrease in serum IgG level after receiving an earlier disease-modifying therapy other than ofatumumab, wherein the earlier disease-modifying therapy comprises an anti-CD20 antibody, and wherein administering ofatumumab (a) slows the decrease of the serum IgG level of the patient relative to the decrease on the earlier disease-modifying therapy; or (b) maintains or increases the serum IgG level of the patient relative to the level of at the start of ofatumumab treatment.
Novartis-COMB157G2302 teaches that Ofatumumab is a fully human anti-CD20 monoclonal antibody (Ab) as recited in instant claims, which is predicted to have low potential for immunogenicity and with very low incidence of anti-drug antibodies against Ofatumumab (p. 17). Novartis-COMB157G2302 teaches a method of treating multiple sclerosis (MS) including relapsing MS, comprising administering to a patient in need thereof an effective amount of an anti-CD20 IgG1 human monoclonal antibody, Ofatumumab, at 20mg by subcutaneous injection three once-weekly loading doses, followed by a maintenance dose of 20mg once monthly as in recited claims 95-97 (see p. 18-21). Novartis-COMB157G2302 also teaches that the ofatumumab is formulated in an amount of 50mg/ml, which is about 20-300mg/ml as in claims 98-99 (see p. 14; p. 28), wherein the multiples sclerosis is relapsing multiple sclerosis (RMS), primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS) as in claims 100-101 (see p.13; p. 15-16; p. 23-24). Novartis-COMB157G2302 teach treatment of Ofatumumab for 96 weeks as in claim 102 (see p. 21).
But Novartis-COMB157G2302 does not teach a patient who has exhibited a decrease in serum IgG level including below a concentration of 900mg/dL, 800mg/dL, below of 700mg/dL or below 80% of the baseline after receiving an earlier disease-modifying therapy other than ofatumumab, wherein the earlier disease-modifying therapy comprises an anti-CD20 antibody recited in claim 64-67, below 80% of the baseline level at the start of the earlier disease-modifying therapy in claim 68,or rituximab or ocrelizumab as an anti-CD20 antibody recited in claim 71, ofatumumab is administered for at least 96 weeks recited in claim 72, administration of ofatumumab maintains or increases the serum IgG level of the patient at no less than 50% of the concentration of 700mg/dL, above the concentration of 700 mg/dL, 800mg/dL, 900mg/dL or administration of ofatumumab maintains or increases the serum IgG level or by about 3% relative to the level at the start of ofatumumab treatment recited in claims 73-74 and 94.
Ancau et al. teach that hypogammaglobulinemia, in particular for IgG defined as IgG < 7g/L (i.e. 700mg/dL) is used for steering dosages and treatment intervals for RTX therapy in autoimmune disorders to avoid the increased risk of serious infections, especially in mid- to long-term anti-CD20 mAb regimens in patients with MS or with NMO-spectrum disorders (NMOSD) (see p. 834, 2nd col., last paragraph to p. 835, 1st col., 1st paragraph). Ancau teaches that “highly active disease-modifying drugs (DMDs) such as RTX (i.e. rituximab, an anti-CD20 monoclonal antibody) have been associated with an increased risk of infections compared to standard DMDs such as interferon-β and glatiramer acetate (IFNβ/GA)” (see p. 835, 2nd col., section 3.1.4, Comparison of RTX to other disease-modifying drugs (DMDs)).
Hallberg et al. teach that MS patients treated with rituximab developed serum IgG levels below 6.7g/L (670mg/dL) and had a decrease in serum IgG levels of 2g/L (200mg/dL) (abstract). The concentration of 670mg/dL and a decrease of 200mg/dL disclosed by Hallberg is below the concentration of 700mg/dL recited in claims 67-68, 76,82-83 and 89-90.
Zoehner et al. teach that the IgG concentrations were lower in patients treated with rituximab, an anti-CD20 monoclonal antibody, as compared to controls. Zoehner teaches that when IgG levels are much lower, at or below 400mg/dl, infections or interference with antibody production generally occur and the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400mg/dl (see abstract). Zoehner teaches that the lower limits of normal (LLN) for serum IgG is <700mg/dL (see abstract; p 3, 1st col., 2nd paragraph). Zoehner teaches that the serum IgG in MS patients is 931 mg/dl (782–1100, n = 327) whereas the serum IgG in control patients is 997 mg/dl (823–1175, n = 58) (p. 3); the serum IgG in secondary progressive MS (SPMS) patients is 690–850mg/dL (average=750mg/dL), the serum IgG in relapsing–remitting MS (RRMS) patients is 800–1110 mg/dL (average= 950mg/dL) and the serum IgG in primary progressive MS (PPMS) patients is 830-1120mg/dL (average=940mg/dL) (p. 3, 2nd col.). The concentration of 750mg/dL disclosed by Zoehner is below a concentration of 900mg/dL or 800mg/dL recited in claims 65-66, 77-78 and 84-85 and 91-92. The concentration of 600mg/dL or 400mg/dL disclosed by Zoehner is below of 700mg/dL or no less than 50% of the concentration of 700mg/dL recited in claims 67-68, 76, 82-83 and 89-90.
A person of ordinary skill in the art would have recognized that selecting and applying the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab (RTX), the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, below a LLN of 700mg/dL, no more than 50% of the concentration of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab and the known technique disclosed by Ancau, Hallberg and Zoehner to the method of Novartis-COMB157G2302 would have yielded the predictable result of treating MS including RMS, PPMS and PRMS, and resulted in an improved method for treating MS.
Treating the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab in the method of Novartis-COMB157G2302 and using the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, below a LLN of 700mg/dL, no more than 50% of a LLN of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving the rituximab in the method of Novartis-COMB157G2302 would monitor and maintain the serum IgG level above a concentration of 700mg/dL, at no more than 50% of 700mg/dL, 800mg/dL or 900mg/dL or increase the serum IgG levels by about 3% relative to the start of Ofatumumab treatment because MS patients treated with rituximab result in a decrease in the serum IgG levels of below a concentration of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, below 800mg/dL or below 900mg/dL, and discontinuation of the treatment with rituximab in MS patients and switching the treatment to Ofatumumab would stop further reduction in the serum IgG levels in MS patients, and would maintain or increase the serum IgG levels at a LLN of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, 800mg/dL or 900mg/dL or increase the serum IgG levels by about 3% relative to the start of Ofatumumab treatment, and would expand application of the method of Novartis-COMB157G2302, and would increase patients’ satisfaction with treatment using an anti-CD30 antibody including Ofatumumab because the MS patients treated with rituximab resulting in a decrease in the serum IgG levels of below a concentration of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, below 800mg/dL or below 900mg/dL; the claimed concentration of the serum IgG levels can be used for monitor treatment of an anti-CD20 antibody to avoid infection, and Ofatumumab which is a fully human anti-CD20 monoclonal antibody (Ab) with low potential for immunogenicity and very low incidence of anti-drug antibodies against Ofatumumab and is a better anti-CD20 antibody for treatment of MS.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab (RTX), the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, below a LLN of 700mg/dL, no more than 50% of the concentration of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab and the known technique disclosed by Ancau, Hallberg and Zoehner to the method of Novartis-COMB157G2302 and yield the predictable result of treating MS and stopping further reduction in the serum IgG levels in MS patients caused by rituximab to maintain or increase the serum IgG levels of the patient at above a LLN of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, above 800mg/dL or above 900mg/dL or increase the serum IgG levels by about 3% relative to Ofatumumab treatment.
Claim Rejections - 35 USC § 103
11. Claim 71 is rejected under 35 U.S.C. 103 as being unpatentable over Novartis-COMB157G2102 in view of Ancau et al. (2019), Hallberg et al. (2019) and Zoehner et al. (2019) as applied to claims 64-68, 71-74 and 76-102 above and further in view of Derfuss et al. (Oral Presentations, Number 65: Serum Immunoglobulin levels and risk of serious infection in the pivotal phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions, p. 20; Multiple Sclerosis J. 2019; 25: (S2) 3-130, cited previously) and Bar-Or et al. (Poster Number p6.1-008, the 72nd Annual Meeting of the American Academy of Neurology, April25-May 01, 2020; Toronto, ON, Canada, cited previously).
Novartis-COMB157G2102, Ancau, Hallberg and Zoehner are set forth above but fail to teach MS patients treated with ocrelizumab (OCR) recited in claim 71.
Derfuss et al. teach that MS patients treated with ocrelizumab (OCR) exhibited a decrease in the serum IgG levels. Derfuss teaches that the decrease in serum IgG levels from baseline to 264 weeks in RMS treated with ocrelizumab (OCR) is 17% (from 1053mg/dL to 879mg/dL), the decrease in PPMS treated with OCR is 16.9% (from 1068mg/dL to 896 mg/dL), and the decrease in serum IgG levels is highly associated with increased rates of serious infection (see abstract). The concentration 879mg/dL or 896 mg/dL is below 900mg/dL recited in claims 66, 78, 85 and 92.
Bar-Or et al. teach MS patients treated with ocrelizumab (OCR) exhibited a decrease in the serum IgG levels, and the rate of the decrease is ~3% from the baseline (see p. 11, Figures).
A person of ordinary skill in the art would have recognized that selecting and applying the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including ocrelizumab (OCR), the known decreased serum IgG levels of below 900mg/dL or 800mg/dL or no more than 50% of the concentration of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving the earlier disease-modifying therapy comprising an anti-CD20 antibody including ocrelizumab (OCR) and the known technique disclosed by Derfuss and Bar-Or to the method of Novartis-COMB157G2302, Ancau, Hallberg and Zoehner would have yielded the predictable result of treating MS including RMS, PPMS and PRMS, and resulted in an improved method for treating MS.
Treating the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including ocrelizumab in the method of Novartis-COMB157G2302, Ancau, Hallberg and Zoehner and using the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, no more than 50% of a LLN of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving the rituximab in the method of Novartis-COMB157G2302, Ancau, Hallberg and Zoehner would monitor and maintain the serum IgG level above a concentration of 700mg/dL, at no more than 50% of 700mg/dL, 800mg/dL or 900mg/dL or increase the serum IgG levels by about 3% relative to the start of Ofatumumab treatment because MS patients treated with ocrelizumab result in a decrease in the serum IgG levels of below 800mg/dL or below 900mg/dL, and discontinuation of the treatment with rituximab in MS patients and switching the treatment to Ofatumumab would stop further reduction in the serum IgG levels in MS patients, and would maintain or increase the serum IgG levels at a LLN of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, 800mg/dL or 900mg/dL or increase the serum IgG levels by about 3% relative to the start of Ofatumumab treatment, and would expand application of the method of Novartis-COMB157G2302, Ancau, Hallberg and Zoehner, and would increase patients’ satisfaction with treatment using an anti-CD30 antibody including Ofatumumab because the MS patients treated with ocrelizumab resulting in a decrease in the serum IgG levels of below a concentration of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, below 800mg/dL or below 900mg/dL; the claimed concentration of the serum IgG levels can be used for monitoring treatment with an anti-CD20 antibody to avoid infection, and Ofatumumab which is a fully human anti-CD20 monoclonal antibody (Ab) with low potential for immunogenicity and very low incidence of anti-drug antibodies against Ofatumumab and is a better anti-CD20 antibody for treatment of MS.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including ocrelizumab, the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, no more than 50% of the concentration of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab and the known technique disclosed by Derfuss and Bar-Or to the method of Novartis-COMB157G2302, Ancau, Hallberg and Zoehner, and yield the predictable result of treating MS and stopping further reduction in the serum IgG levels in MS patients caused by ocrelizumab to maintain or increase the serum IgG levels of the patient at above a LLN of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, above 800mg/dL or above 900mg/dL or increase the serum IgG levels by about 3% relative to Ofatumumab treatment.
Double Patenting
12. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 64-68, 71-74 and 76-102 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 20-25, 28-32, 38, 42-44 and 47-93 of copending Application No. 17/753632, claims 1, 4-5, 27, 31-37, 40-41 and 54-57 of copending Application No. 17/753,635, claims 26-45 of copending Application No. 18/286,030, or claims 16-36 copending Application No.18/683858 in view of Novartis-COMB157G2102, Ancau (2019), Hallberg (2019), Zoehner (2019), Derfuss (2019) and Bar-Or (2020).
Claims 1-11, 20-25, 28-32, 38, 42-44 and 47-93 of Application No. 17/753632 (the ‘632 Application) claim a method of treating relapsing multiple sclerosis, comprising administering ofatumumab to a patient who has been treated with a disease-modifying therapy other than ofatumumab, wherein the disease-modifying therapy includes anti-CD20 therapy including ocrelizumab or rituximab (claims 70-75).
Claims 1, 2, 4-7, 9, 18-21, 27, 31-37, 40-41 and 54-57 of Application No. 17/753635 (the ‘635 Application) claim a method of treating relapsing multiple sclerosis (RMS), comprising administering ofatumumab to a patient in need thereof an effective amount of ofatumumab and a vaccine, thereby treating or preventing RMS, and wherein the patient is treated with an immunosuppressive agent other than Ofatumumab including an antibody, rituximab (claims 9, 13, 18-19).
Claims 26-45 of Application No. 18/286,030 (the ‘030 Application) claim a method of treating multiple sclerosis (MS) in a patient, comprising administering a therapeutically effect amount of ofatumumab to the patient wherein the patient is of Asian race, wherein serum IgG levels are maintained in the range of 900-1400mg/dl during the treatment and the ofatumumab is administer at a dose of 20mg every 4 weeks or administering 20mg at weeks 0, 1 and 2 and MS includes relapsing MS, CIS, RRMS and SPMS, and a premedication is administered to the patient prior to the first dose of ofatumumab.
Claims 16-36 of Application No. 18/683,858 (the ‘858 Application) claim a method of treating multiple sclerosis (MS), comprising administering ofatumumab to a patient who has at most 40kg body weight and/or aged between 5 and <18 years, wherein the patient includes a patient who has received an MS disease-modifying therapy other than ofatumumab including anti-CD20 therapy including ocrelizumab or rituximab (claim 26-27).
While the claims of the ‘632 Application, the ‘635 Application, the ‘030 Application and the ‘858 Application do not explicitly recite that the patient has exhibited a decrease in serum IgG level including below a concentration of 900mg/dL, 800mg/dL, below a concentration of 700mg/dL or below 80% of the baseline after receiving an earlier disease-modifying therapy other than ofatumumab wherein the earlier disease-modifying therapy comprises an anti-CD20 antibody including rituximab or ocrelizumab recited in claim 64-67, below 80% of the baseline level at the start of the earlier disease-modifying therapy in claim 68,or rituximab or ocrelizumab as an anti-CD20 antibody recited in claim 71, ofatumumab is administered for at least 96 weeks recited in claim 72, administration of ofatumumab maintains or increases the serum IgG level of the patient at no less than 50% of the concentration of 700mg/dL, above the concentration of 700 mg/dL, 800mg/dL, 900mg/dL or administration of ofatumumab maintains or increases the serum IgG level or by about 3% relative to the level at the start of ofatumumab treatment recited in claims 73-74 and 94 or continuing treatment for at least 96 weeks as in claims 72 and 102, Novartis-COMB157G2102, Ancau, Hallberg, Zoehner, Derfuss and Bar-Or teach these limitations and provide motivation and an expectation of success for the reasons set forth above.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known the known patients who have exhibited a decrease in the serum IgG levels in MS patients after being treated with an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab (RTX), the known decreased serum IgG levels of below 900mg/dL, 800mg/dL, below a LLN of 700mg/dL, no more than 50% of the concentration of 700mg/dL, or below 80% of the baseline or with a reduction rate of about 3% after receiving an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab and the known technique disclosed by Novartis-COMB157G2102, Ancau, Hallberg, Zoehner, Derfuss and Bar-Or to the method of the ‘632 Application, the ‘635 Application, the ‘030 Application, or the ‘858 Application, and yield the predictable result of treating MS and stopping further reduction in the serum IgG levels in MS patients caused by an earlier disease-modifying therapy comprising an anti-CD20 antibody including rituximab or ocrelizumab to maintain or increase the serum IgG levels of the patient at above a LLN of 700mg/dL, at no more than 50% of a LLN of 700mg/dL, above 800mg/dL or above 900mg/dL or increase the serum IgG levels by about 3% relative to the level of the start of Ofatumumab treatment.
Conclusion
13. NO CLAIM IS ALLOWED.
14. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
August 26, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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