Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-14 are pending and under examination.
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.
Claims 1-10 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Stahl (20040259771) in view of Ardehali et al. (J Thorac Cardiovasc Surg. 2003 Dec;126(6):1929-34), Rossi et al. (JBC, Vol. 276, No. 44, Issue of November 2, pp. 40880–40887, 2001), Rieben et al. (Blood. 1999 Feb 1;93(3):942-51), Simon et al. (Allergy 2003: 58: 543–552), Carter et al. (6407213), Harlow et al., Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, pp 44, 45 and 52), and Buechler et al. (20030091995) (all cited on an IDS).
As preliminary matter, note that SEQ ID NO: 6 = the C-terminal portion of human MASP-2 comprising the CCP1-CCP2-serine protease domains of human MASP-2.
Stahl teaches a method of inhibiting MASP-2-dependent complement activation in a subject who has received a tissue injury associated with transplantation comprising intravenously administering to the subject an amount of a monoclonal or humanized anti-MASP-2 antibody effective to inhibit MASP-2-dependent complement activation (see paragraphs 9, 10-12, 34, 40, 45 and 109 and claims 6, 29, 44, 56 and 74).
Moreover, Stahl teaches / demonstrates complement activation in human vascular endothelial cells following endothelial hypoxia/reoxygenation is mediated by the lectin complement pathway independent of natural antibody or C1, i.e., independent of the classical complement pathway (see paragraph 36 and Example 6).
Ardehali teaches ischemia-reperfusion injury was known to be a major cause of mortality and morbidity in allograft lung transplantation. Moreover, one mechanism believed to cause ischemia-reperfusion injury was the interaction of activated leukocytes with injured graft endothelial cells, which is, in part, driven by complement activation (see Abstract, Introduction and Material and Methods).
Rossi teaches MASP-2 specifically cleaves complement proteins C2 and C4, and, with respect to the latter, MASP-2 cleaves C4 much more efficiently than does C1s, emphasizing its physiological relevance with respect to complement activation (see Abstract, page 40880-1 bridging paragraph and page 40887, left col., last paragraph).
Given the reference teachings it would have been obvious to one of ordinary skill in the art to inhibit MASP-2 dependent complement activation in a subject that has undergone, is undergoing, or will undergo an allogeneic lung transplant procedure comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation so as to ameliorate ischemia-reperfusion injury of the lung endothelial cells. One of ordinary skill in the art would have been motivated to do so given the need in the art for effective treatments as discussed by Ardehali. Moreover, and one of ordinary skill in the art would have had a reasonable expectation of successfully doing so given the teachings of Stahl concerning the role of the lectin complement pathway in ischemia-reperfusion injury, including in the context of human vascular endothelial cells, and further given the teachings of Rossi that MASP-2 is the physiologically relevant MBL-associated serine protease for C4 and C2 cleavage. Note in this regard that it would likewise have been obvious to one of ordinary skill in the art to ensure that any MASP-2 inhibitory bind to the SEQ ID NO: 6 portion of the protein since this sequence comprises the serine protease domain.
Insofar as Stahl does not explicitly teach using a MASP-2 inhibitory agent that selectively inhibits MASP-2-dependent complement activation without substantially inhibiting C1q-dependent complement activation, wherein the MASP-2 inhibitory agent specifically binds to a polypeptide comprising SEQ ID NO: 6 with an affinity of at least 10 times greater than it binds to a different antigen in the complement system, and has reduced effector function please consider the following additional teachings.
One of ordinary skill in the art was well aware that intravenously administered immunoglobulins have the ability to inhibit C1q-dependent complement activation by binding to C1q and diverting it from acting on its natural targets (see, e.g., Rieben Introduction on page 942, as well as Simon Figure 1 for an illustration of how C1q binds to the Fc portion of an antibody).
Thus, in following the teachings of Stahl, Ardehali and Rossi to inhibit MASP-2 dependent complement activation in a subject that has undergone, is undergoing, or will undergo an allogeneic lung transplant procedure comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation so as to ameliorate ischemia-reperfusion injury of the lung endothelial cells one of ordinary skill in the art would have been motivated to minimize as much as possible unnecessary disturbance of the classical induction pathway of complement so that this branch of the innate immune response can continue to perform its physiologic role in responding to infection.
Moreover, it would have been obvious to one of ordinary skill in the art that there are multiple ways of achieving this goal.
For example, it would have been obvious to one of ordinary skill in the art that by making anti-MASP-2 antibodies having sufficiently high affinity and specificity for their target antigen as well as a long serum half-life, e.g., by making a specific, high-affinity, fully human anti-MASP-2 antibody, one of ordinary skill in the art could administer the antibody at sufficiently low concentrations so as to inhibit MASP-2 without substantially inhibiting C1q-dependent complement activation.
Moreover, it further would have been obvious to one of ordinary skill in the art that an anti-MASP-2 antibody having an Fc isotype that does not bind C1q, i.e., is not able to mediate complement dependent cytotoxicity via C1q binding, could be used. This concept is generally described by the teachings of Carter at col. 8, 5th paragraph (emphasis added): “The humanized antibody will be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and lgG4. Usually the constant domain is a complement fixing constant domain where it is desired that the humanized antibody exhibit cytotoxic activity, and the class is typically IgG.sub.1. Where such cytotoxic activity is not desirable, the constant domain may be of the IgG2 class. The humanized antibody may comprise sequences from more than one class or isotype, and selecting particular constant domains to optimize desired effector functions is within the ordinary skill in the art.”
In summary, given the reference teachings and the ordinary creativity of the skilled artisan it was obvious to one of ordinary skill in the art that when treating a condition related to MASP-2 activity comprising administration of an anti-MASP-2 antibody, it would be reasonable to either i) produce an anti-MASP-2 antibody that can be dosed at levels low enough that the effect on C1q is minimal or ii) make an IgG2 form of the anti-MASP-2 antibody.
Furthermore, with respect to (i) above, there are many art recognized techniques for determining antibody specificity and affinity, and it would have been obvious to one of ordinary skill in the art that when making a targeted agent for therapeutic use, such as an anti-MASP-2 antibody, said antibody should bind the target antigen at least 10 times better than it does different antigens. One of ordinary skill in the art would have had a reasonable expectation of success in doing so consistent with the teachings of Harlow at pages 44, 45 and 52 that cross reactions are less common when the antigen is the native protein and that antibodies suitable for methods requiring recognition of native protein can be easily screened to identify those that have good selectivity.
Lastly, with respect to using recombinant anti-MASP-2 antibodies, while the teachings of Stahl, Ardehali and Rossi are directed to using monoclonal or humanized anti-MASP-2 antibodies to inhibit to MASP-2 dependent complement activation in a subject that has undergone, is undergoing, or will undergo an allogeneic lung transplant procedure comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2 dependent complement activation so as to ameliorate ischemia-reperfusion injury of the lung endothelial cells, the ordinarily skilled artisan recognizes that polyclonal antibodies while lacking the homogeneity of monoclonal antibodies also have some advantages, e.g., they can often bind and neutralize multiple disparate epitopes in the polypeptide against which they are selected (see, e.g., Buechler at paragraphs 124-125). Moreover, Buechler teaches therapeutic polyclonal antibodies with ultra-high affinity and superior specificity can be successfully generated using phage display (see, e.g., Buechler at page 4, right col., page 11, paragraph 103; pages 14-15, paragraphs 126-128).
Given the reference teachings it would have been obvious to one of ordinary skill in the art that recombinant polyclonal anti-MASP-2 antibodies generated by the phage display method of Buechler could be successfully substituted for monoclonal or humanized anti-MASP-2 antibodies taught by Stahl.
Such a modification of the teachings of Stahl merely represents the simple substitution of one known, equivalent element for another to obtain predictable results, i.e., inhibition of MASP-2-dependent complement activation (see MPEP § 2143, part B). Moreover, given the multi-domain organization of MASP-2, one of ordinary skill in the art would have been motivated to prepare recombinant polyclonal anti-MASP-2 antibodies because they provide the advantage of inhibiting more than one MASP-2 functional domain simultaneously.
Thus, 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, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 11-14 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Stahl (20040259771) in view of Ardehali et al. (J Thorac Cardiovasc Surg. 2003 Dec;126(6):1929-34), Rossi et al. (JBC, Vol. 276, No. 44, Issue of November 2, pp. 40880–40887, 2001), Rieben et al. (Blood. 1999 Feb 1;93(3):942-51), Simon et al. (Allergy 2003: 58: 543–552), Carter et al. (6407213), Harlow et al., Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, pp 44, 45 and 52), and Buechler et al. (20030091995)(all cited on an IDS), as applied to claims 1-10 above, and further in view of Baldwin et al. (Transplantation, Volume 68(6), 27 September 1999, pp 894-900)(cited on an IDS).
The teachings of Stahl in view of Ardehali, Rossi, Rieben, Simon, Carter, Harlow and Buechler are given above.
It would have been obvious to one of ordinary skill in the art attempting to prolong graft survival in a subject that will undergo an allogeneic lung transplant to administer monoclonal masp-2 inhibitor antibody prior to the transplant procedure because the process of lung transplantation often requires circulation of the patient’s blood via a cardiopulmonary bypass machine (CBP). Thus, the skilled artisan would want to ensure widespread, fully penetrate inhibition of masp-2 throughout the circulatory system prior to CBP-mediated circulation so as to ensure masp-2 inhibition as soon as reperfusion of the transplanted lung occurs.
With respect to administering a masp-2 antibody during the transplant procedure as recited in claim 12, it would have been obvious to do so for a variety of reasons, e.g., to ensure sustained maximal masp-2 inhibition and further because, as taught by Stahl, LCP-associated complement activation can also occur during cardiopulmonary bypass (see paragraph 34 and claim 44).
As to administering the masp-2 antibody during the acute period following the transplant procedure (claim 13) or as a long time post-transplantation therapy as recited in claim 14, it would have been equally obvious to the ordinarily skilled artisan to administer the monoclonal MASP-2 inhibitory antibody to the transplant recipient during the acute period following the transplant procedure, or as a long term post-transplantation therapy, so as to maintain suppression of the lectin pathway given the possibility that de novo complement activation could be occurring for weeks after transplantation as described by Baldwin at page 10, 3rd paragraph.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
Prosecution Insights