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 .
Claims 1-10 are pending and under examination.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 and 3-7 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Schwaeble et al. (AU2013201558, cited herewith) as evidenced by Mousavi et al. (Iranian Journal of Kidney Diseases, (November 2011) Vol. 5, Supp. SUPPL. 2, pp. 24. Abstract Number: P201, cited herewith) and Sam et. al. (Clin Exp Nephrol (2015) 19:395–402, cited herewith).
Claim 1 of Schwaeble is drawn to, “A MASP-2 inhibitory agent for use in the treatment of a subject suffering from…(ii) a MASP-2 dependent complement-mediated renal condition selected from the group consisting of…membranous glomerulonephritis…wherein the MASP-2 inhibitory agent is an anti-MASP-2 antibody or fragment thereof that specifically binds to a portion of SEQ ID NO:6.”
SEQ ID NO: 6 of Schwaeble is drawn to the human MASP-2 protein (see page 14, line 2).
Claim 2 of Schwaeble specifies that the “…MASP-2 inhibitory agent for use as claimed in Claim 1, wherein the composition comprises a MASP-2 inhibitory agent which selectively inhibits MASP-2-dependent complement activation without substantially inhibiting C1q dependent complement activation,” meaning that the MASP-2 inhibitory agent is one that does not substantially inhibit the classical pathway of complement.
Claims 6-9 of Schwaeble further set forth that the MASP-2 inhibitory agent for use as claimed in any preceding claim is an anti-MASP-2 antibody which “is monoclonal,” or “is recombinant,” or “has reduced effector function,” or “is chimeric, humanized or human”:
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As evidenced by the teachings of Sam, the phrases “membranous glomerulonephritis” and “membranous nephropathy” were often used synonymously prior to applicant’s earliest filing date, e.g.,:
“More than 50 years ago, it was recognized that there are a group of patients with membranous GN who have pathological features of lupus nephritis, but not a diagnosis of systemic lupus erythematosus (SLE). In 1964, Simenhoff and Merrill stated that “lupus nephritis may present as a renal syndrome only, without any of the other manifestations of SLE [1].” The problem with labeling these patients as renal-limited lupus is that systemic lupus suggests a ‘systemic disease’ that is not limited to one organ. It is likely that the pathogenesis of membranous nephropathy is autoimmune, thus stating that these patients have renal-limited lupus adds little to current understanding and natural history of this disease. It is true that some of the patients labeled as “latent lupus” and not SLE at the time of kidney biopsy subsequently were diagnosed with SLE years later. However, the criteria for diagnosing SLE have changed over the years (many of the patients with latent lupus were diagnosed using the LE cell preps which are no longer used), and it is not documented what percentage of patients with pathological features of membranous lupus nephritis but no diagnosis of SLE subsequently developed SLE. At the time of kidney biopsy, it is important to determine if membranous GN is primary or secondary in nature, because pathogenesis, treatment response and prognosis differ in each disease group. We evaluated 98 patients with membranous nephropathy and attempted to determine renal prognosis depending on whether they have idiopathic, lupus or ‘lupus-like’ membranous GN.”
(see Introduction, emphasis added).
“The percentage of all the cases of membranous GN caused by membranous lupus nephritis varies between the different studies, although the average of these studies is 24 % while 62 % were idiopathic membranous GN [9, 12–19]. There were 1368 patients with membranous GN in all of these studies. Other secondary causes accounted for another 14 % of membranous GN cases. Interestingly, in one Chinese study of 390 patients with membranous nephropathy, 12.1 % of the patients had hepatitis B, which is close to the 11 % incidence of hepatitis B in the general Chinese population [13, 20]. In the same study, the incidence of malignancy-associated membranous nephropathy was 3.1 %, which is somewhat lower than the 8.4 % incidence found by Burstein et al. in 1993 [13, 21]. Thus, even though hepatitis B and malignancy are likely implicated in membranous GN, it should be emphasized that they are uncommon causes (more often association rather than true causation), whereas SLE is a common cause of membranous GN.” (see Discussion, 2nd paragraph, emphasis added).
Similar use of these phrases in a synonymous manner is also evident in the Abstract of Mousavi (emphasis added):
Introduction. Idiopathic membranous glomerulonephritis is one of the glomerular diseases that are well described to recur after kidney transplantation, with most studies reporting rates between 10 and 45 percent. Unfortunately, there is no definitive therapy for recurrent membranous nephropathy in the graft and affected patients progress to end-stage renal failure at a mean of four years. There are few case reports that the administration of Rituximab is effective in the treatment and alters the course of recurrent disease. Case Report. A 36-year old male with end-stage renal disease whose primary kidney disease was idiopathic membranous glomerulonephritis underwent living unrelated kidney transplantation and he was maintained on the immunosuppressive regimen: Cyclosporine, Mycophenolate Mofetil, and Prednisolone. Two years later, he developed frank nephrotic syndrome with 8.5 g/d of proteinuria and normal serum creatinine. Allograft biopsy showed recurrence of membranous nephropathy and in addition to Captopril, Losartan and Atorvastatinhe received four weekly doses of Rituximab (375 mg/ m2). Although the rate of proteinuria has reduced in 1, 3, and 5 months later; however, he still has nephrotic range proteinuria (3.5 to 4.5 g/d). Conclusions. This case suggests that four weekly doses of Rituximab (375 mg/m2) cannot induce complete remission of recurrent membranous glomerulonephritis after kidney transplantation.
Given that the ordinarily skilled artisan understood membranous glomerulonephritis to be synonymous with membranous nephropathy prior to applicant earliest filed application, the teachings of Schwaeble set forth above plainly anticipate at least claims 1 and 3-5.
Moreover, with respect to claim 6, given that Schwaeble teaches the treatment of a subject suffering from membranous glomerulonephritis by administering an anti-MASP-2 antibody it also stands to reason that the subject being treated has been identified as a human subject having membranous glomerulonephritis / membranous nephropathy prior to treatment. Furthermore, given that the treatment of membranous glomerulonephritis / membranous nephropathy is measured by the extent to which protein is detected in the urine due to defective renal filtering (“proteinuria”) as evidenced by the teachings of Mousavi (see entire document) and Sam (see, e.g., at page 396-97 bridging paragraph; at page 397-98 bridging paragraph; at page 399-400 bridging paragraph), which are reflective of the knowledge of the one of ordinary skill in the art, it stands to reason that the ordinarily skilled artisan treating membranous glomerulonephritis / membranous nephropathy according to the teachings of Schwaeble would be administering sufficient anti-MASP-2 antibody to improve renal function as recited in claims 6 and 7.
In conclusion, the teachings of Schwaeble anticipate claim 1 and 3-7 for the reasons set forth above.
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.
Claim(s) 2 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Schwaeble et al. (AU2013201558) as applied to claims 1 and 3-7 above, and further in view of Sam et. al. (Clin Exp Nephrol (2015) 19:395–402) and Johns Hopkins “Lupus Immunosuppressive Medications” captured from the internet on December 15, 2014, pages 1-17 (cited herewith).
The teachings of Schwaeble are set forth above.
However, Schwaeble does not explicitly teach treating a human subject “suffering from steroid-dependent membranous nephropathy,” or treating a human subject suffering from membranous nephropathy in order to “decrease the corticosteroid dosage in said subject,” as recited in claims 2 and 9, respectively.
With respect to treating a human subject “suffering from steroid-dependent membranous nephropathy” at page 172, 3rd full paragraph, while corticosteroids are often used to treat membranous nephropathy, there was a need for in the art for “alternative therapies.”
Moreover, as taught by Johns Hopkins “Lupus Immunosuppressive Medications” captured from the internet on December 15, 2014, pages 1-17, in general, “…immunosuppressive medications are given in addition to or instead of steroid therapy to lower the dose of steroids needed and thus spare some of the undesirable side effects of steroid therapy. For this reason, these drugs are sometimes called ‘steroid-sparing’ medications or ‘adjuvant’ (helping) drugs.”
(see page 2 at 2nd paragraph).
Furthermore, as shown in Sam Tables 3 and 6 of Sam, the vast majority of patients having membranous glomerulonephritis / membranous nephropathy were treated with combinations of immunosuppressive agents which include prednisone / steroids.
Taking the teachings set forth above together with those of Schwaeble, it further would have been obvious to the ordinarily skilled artisan that supplementing immunosuppressive combination therapy for the treatment of membranous glomerulonephritis / membranous nephropathy with an anti-MASP-2 antibody as taught by Schwaeble should allow for a steroid-sparing effect.
Thus, it would have been obvious to one of ordinary skill in the art to treat a subject suffering from prednisone / steroid-dependent membranous glomerulonephritis / membranous nephropathy with the anti-MASP-2 antibody as taught by Schwaeble with a reasonable expectation that doing so will lower the dose of steroids needed and thus spare some of the undesirable side effects of steroid therapy.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Schwaeble et al. (AU2013201558) as applied to claims 1 and 3-7 above, and further in view of Sam et. al. (Clin Exp Nephrol (2015) 19:395–402, cited herewith) and Zhang et al. (Lupus (2015) 24, 943–947, cited herewith).
The teachings of Schwaeble as applied to claims 1 and 3-7 are set forth above.
However, Schwaeble does not explicitly teach treating a human subject “suffering from membranous nephropathy (MN) comprising administering to the subject a composition comprising an amount of a MASP- 2 inhibitory antibody, or antigen-binding fragment thereof, effective to inhibit MASP-2- dependent complement activation, wherein the MASP-2 inhibitory antibody or antigen- binding fragment thereof is administered in an amount effective and for a time sufficient to achieve at least a 20 percent reduction in 24-hour urine protein excretion as compared to baseline 24-hour urine protein excretion in the subject prior to treatment.”
As described in the paragraphs bridging pages 399-400 and 400-401 of Sam, as well as in Table 6 on page 440, the primary measure for monitoring the extent of kidney dysfunction in membranous glomerulonephritis / membranous nephropathy is via measurement of proteinuria.
Moreover, as described by Zhang in the first few sentence of the Introduction, “Quantifying proteinuria accurately and precisely is vital in the monitoring disease activity in patients with lupus nephritis (LN).1,2 The gold standard to assess proteinuria is the protein content of an accurately collected 24 h urine.3,4” Furthermore, as set forth in the Discussion of Zhang describing various studies (as well as their own) where “spot” proteinuria measurement was compared to the “standard total 24-h urine protein excretion” measurement, it would be evident to one of ordinary skill in the art that, in general, 24-h urine protein excretion is the most accurate way to assess kidney function in any disease the kidney is failing to keep larger proteins out of the urine.
Given the teachings of Schwaeble in view of Sam and Zhang it would have been obvious to one of ordinary skill in the art to measure 24-h urine protein excretion (as compared to a baseline value prior to treatment) in a membranous glomerulonephritis / membranous nephropathy patient being treated with an anti-MASP-2 antibody so as to assess treatment effectiveness.
Insofar as Sam does not explicitly point to an “at least 20 percent reduction in 24-hour urine protein excretion as compared to baseline…,” it would have been evident to one of ordinary skill in the art wishing to treat a subject suffering from the MASP-2 dependent complement-mediated renal condition which is membranous glomerulonephritis by administering a MASP-2 inhibitory antibody that specifically binds to a portion of SEQ ID NO:6 (as taught by Schwaeble) that they should act to optimize drug dosages and administration schedules to have the greatest possible effect on proteinuria. It is not inventive to claim a particular effect of treatment on 24-hour urine protein excretion as the discovery of an optimum value or workable range when such a result is no more than a results effective variable that is ordinarily measured by those of ordinary skill in the art as exemplified by the teachings of Sam and Zhang set forth above. In this regard it is noted that it is a well settled principal that “[d]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." See Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results). See also MPEP § 2144.05 part II.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Schwaeble et al. (AU2013201558) as applied to claims 1 and 3-7 above, and further in view of Cummings et al. (20150017162, cited herewith).
The teachings of Schwaeble as applied to claims 1 and 3-7 are set forth above.
However, Schwaeble does not explicitly teach treating a human subject “suffering from membranous nephropathy (MN) comprising administering to the subject a composition comprising an amount of a MASP- 2 inhibitory antibody, or antigen-binding fragment thereof, effective to inhibit MASP-2- dependent complement activation, wherein the MASP-2 inhibitory antibody or antigen- binding fragment thereof, wherein the MASP-2 inhibitory antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDR- H1, CDR-H2 and CDR-H3 of the amino acid sequence set forth as SEQ ID NO:67 and a light chain variable region comprising CDR-L1, CDR-L2 and CDR-L3 of the amino acid sequence set forth as SEQ ID NO:69.”
Cummings describes a MASP-2 inhibitory antibody comprising the CDRs recited in claim having the clone name “17D20m_d3521N11,” said antibody comprising the Vh and Vl domains of SEQ ID NOs: 111 and 115 (see Tables 8A-F, 10A-F, 18 and 19). The“17D20m_d3521N11,” antibody of Cummings comprising the Vh and Vl domains of SEQ ID NOs: 111 and 115 comprises the CDRs of SEQ ID NOs: 67 and 69, respectively, of the instant claims.
At page 111, 1st full paragraph, Cummings teaches, “[a] functional assay that measures inhibition of lectin pathway C3 convertase formation was used to evaluate the "blocking activity" of the MASP-2 scFv candidate clones. MASP-2 serine protease activity is required in order to generate the two protein components (C4b, C2a) that comprise the lectin pathway C3 convertase. Therefore, a MASP-2 scFv that inhibits MASP-2 functional activity (i.e., a blocking MASP-2 scFv), will inhibit de novo formation of lectin pathway C3 convertase….,” and in Table 7 Cummings shows that the “17D20m_d3521N11” antibody has the greatest ability to inhibit lectin pathway C3 convertase formation in said assay (as measured by diminished C3 convertase catalyzed formation of C3b).
Moreover, at page 125, 1st full paragraph, Cummings describes how the mAb#6 antibody is highly specific for MASP-2.
Given the reference teachings it would have been obvious to the ordinarily skilled artisan, and the ordinarily skilled artisan would have been motivated to make use of the MASP-2 inhibitory antibody comprising SEQ ID NOs: 111 and 115 described by Cummings to treat a human subject suffering from membranous glomerulonephritis / membranous nephropathy since the “17D20m_d3521N11” antibody has the greatest ability to inhibit lectin pathway C3 convertase formation, and is further taught by Cummings do so with greater specificity for MASP-2.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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