Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Claims 1-13 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 of this title, 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 negatived by the manner in which the invention was made.
Claims 1, 2, 4, 7, 8, 11 and 13 are rejected under 35 U.S.C. 103(a) as being unpatentable over Stahl (US 20040259771) in view of the knowledge in the art as evidenced by Collard et al. (Am J Pathol 2000, 156:1549–1556), Rossi et al. (JBC, Vol. 276, No. 44, Issue of November 2, pp. 40880–40887, 2001), Chen et al. (JBC, Vol. 279, No. 25, pp. 26058–26065, 2004, epub March 1, 2004), Pedersen et al. (Clin Exp Immunol, June 8 2004; 137:117–122), De Simoni et al. (American Journal of Pathology, Vol. 164, No. 5, May 2004, 1857-1863), Ambrus et al. (The Journal of Immunology, 2003, 170: 1374–1382), the alignments attached to the instant office action, Moller-Kristensen et al. (Journal of Immunological Methods 282 (2003) 159– 167) and Harlow et al. (Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, pp 44, 45 and 52)(all cited on an IDS).
The knowledge in the art of complement in ischemia-reperfusion pathogenesis
Prior to applicant’s date of invention it was known in the art that human vascular endothelial cells (HuVECs) subjected to oxidative stress in the presence of 30% human serum exhibit colocalized C3 and MBL deposition which can be strongly attenuated by inclusion of an antagonistic anti-MBL antibody (see Collard et al., “Binding of MBL to Hypoxic HUVECs” starting on page 1553 and Fig. 7).
With respect to ischemic stroke in particular, Pedersen taught a marker of complement activation, the soluble terminal complement complex (TCC, a.k.a. “soluble terminal SC5b-9 complement complex”), as well as a known activator of the complement System, C-reactive protein (CRP), are over-produced in the plasma of patients having acute ischemic stroke for as many as 12 days post-stroke (see Figs 1 and 3).
While Pedersen speculated that CRP may have an effect on the classical pathway of complement in acute ischemic stroke, De Simoni showed, at least in a mouse model system based on transient focal cerebral ischemia achieved by middle cerebral artery occlusion, i.e., a mouse model system of acute ischemic stroke (see page 1858, left col., last paragraph), that ischemia-reperfusion brain injury did not depend on the presence of C1q (see, e.g., Fig. 5).
Moreover, Ambrus taught that the C1-inh which treats ischemia-reperfusion brain injury in the C1q-/- mouse model of De Simoni (see, e.g., Fig. 5) is capable of binding MASP-2 with high affinity and blocking its proteolytic function (see page 1381, left col., 2nd paragraph).
Thus, the knowledge in the art prior to applicant’s date of invention suggested role for the lectin complement pathway in acute ischemia-reperfusion brain injury.
With the above in mind the teachings of Stahl and the prima facie case of obviousness are as follows:
Stahl teaches a method of inhibiting the lectin complement pathway in a stroke patient, or in a subject suffering from ischemia-reperfusion injury such as a cardiopulmonary bypass patient, a transplantation patient, a myocardial infarction patient comprising intravenously administering a monoclonal or humanized anti-MASP-1 or MASP-2 antibody in an amount effective to mitigate the cellular injury associated with stroke or with ischemia and reperfusion (see paragraphs 9-12, 18, 34, 36, 40, 42, 45 and 109 and claims 6, 29, 44, 56 and 74). Furthermore, given the knowledge in the prior art illustrated by the teachings of Pedersen that the post-stroke period is associated with activation of the complement system for as many as 12 days post-stroke, it would have been obvious to one of ordinary skill in the art that the teachings of Stahl are also applicable to a patient suffering from an ischemia-reperfusion injury subsequent to stenting to allow for post-stroke hemodynamic resuscitation, consistent with claim 13.
Moreover, Stahl demonstrates complement activation in human vascular endothelial cells (HuVECs) following endothelial hypoxia/reoxygenation can be mediated by the lectin complement pathway independent of natural antibody or C1, i.e., independent of the classical complement pathway (see Example 6). This experiment shows an MBL ligand exposed on human endothelial cells by ischemia/reperfusion injury is capable of triggering MBL/MASP induced assembly of the C3 convertase and generation of C3b.
However, Stahl does not explicitly teach a method a method of treating a subject suffering from, or at risk of developing, an ischemia-reperfusion injury comprising administering to the subject a monoclonal MASP-2 inhibitory-antibody, or antigen-binding fragment thereof, that specifically binds to a portion of SEQ ID NO:6 and inhibits MASP-2-dependent complement activation.
That said, first, while Stahl describes treating the cellular injury associated with stroke or ischemia and reperfusion with a lectin complement pathway inhibitor, given the teachings of Stahl as viewed through the lens of the knowledge in the prior art, it would have been obvious to one of ordinary skill in the art that when selecting a stroke patient to treat according to the teachings of Stahl one should select a patient having an acute ischemic stroke rather than a hemorrhagic stroke. This is because the references suggest the lectin complement pathway will be active at the endothelial cell surface of a patient suffering from an acute ischemic stroke and the subsequent reperfusion injury. One of ordinary skill in the art would have been motivated to do so, and would have had a reasonable expectation of successfully doing so given the knowledge in the art linking cerebral ischemia and reperfusion injury to activation of the lectin complement pathway.
Secondly, while Stahl teaches the use of anti-MASP-1 or MASP-2 inhibitory antibodies as possible agents to inhibit the lectin complement pathway in a stroke patient, the ordinarily skilled artisan would not recognize these agents as functional equivalents.
Rather, with respect to inhibiting the lectin complement pathway with a MASP-2 inhibitory antibody in particular, Rossi teaches that in contrast to MASP-1, the cleavage activity of MASP-2 is responsible for initial event in the formation of the C3-convertase (C4b2a) which is the limiting step of this process (see page 40886 col. bridging paragraph). Rossi also teaches that while both MASP-1 and MASP-2 can mediate C2 cleavage (the second event in the formation of the C3-convertase), the C2 cleavage activity of MASP-1 is quite negligible compared with that of MASP-2 (20,000-fold less) (see page 40887, left col., 1st full paragraph).
Similar to Rossi, Chen teaches the critical endpoint of the lectin complement pathway is production of the C3 convertase composed of C4bC2a which, in turn, activates the downstream terminal complement pathway ultimately leading to neutralization of the target cell (see Introduction and Fig. 12). Moreover, as further described by Chen, activated MASP-1, even at higher concentration, cannot cleave C4 to yield the C4b polypeptide (see page 26061-2 bridging paragraph), which is the critical initiation step of the lectin complement pathway.
Thus, it would have been obvious to one of ordinary skill in the art that a MASP-2 inhibitory antibody would be superior to a MASP-1 inhibitory antibody for mitigating the cellular injury associated with ischemia-reperfusion in a patient in need thereof.
Moreover, with respect to using a MASP-2 antibody that selectively inhibits MASP-2 dependent complement activation without substantially inhibiting C1q-dependent complement activation, given the structurally similarities between MASP-2 and a number of other complement proteins – MASP-1, MASP-3, C1r and C1s (see attached alignments) – it would have been a particular concern to the ordinarily skilled artisan making a MASP-2 inhibitory antibody that the antibody bind with high affinity and specificity to MASP-2, consistent with claim 4.
One reason the skilled artisan would have been motivated to prepare such an antibody is to avoid unwanted binding to the C1r/C1s proteases of the classical complement pathway thereby not interfering with the protective role of these proteins in fighting diverse pathogens.
Yet another reason the skilled artisan would have been motivated to avoid cross-reactivity with, e.g., MASP-1/MASP-3, is because MASP-2 was known to be one of the least abundant complement proteins in serum as described in the instant specification at page 244, 1st full paragraph and as evidenced by Moller-Kristensen at Fig. 3. Thus, cross-reactivity with MASP-1/MASP-3 would be expected to merely dilute the desired inhibitory effect on MASP-2. When the above is taken together, it would have been obvious to one of ordinary skill in the art to make and use an inhibitory anti-MASP2 antibody having high MASP-2 affinity and specificity.
Moreover, 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.
Thus, the skilled artisan would have been motivated to inhibit MASP-2 dependent complement activation in a subject that has recently had or is having, e.g., a cerebral ischemia-reperfusion injury / acute ischemia-reperfusion stroke with an anti-MASP-2 antibody that selectively inhibits MASP-2 dependent complement activation without substantially inhibiting C1q-dependent complement activation.
In conclusion, 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.
Claims 1, 2, 4, 6-8, 11 and 13 are rejected under 35 U.S.C. 103(a) as being unpatentable over Stahl (US 2004/0259771) in view of the knowledge in the art as evidenced by Collard et al. (Am J Pathol 2000, 156:1549–1556), Rossi et al. (JBC, Vol. 276, No. 44, Issue of November 2, pp. 40880–40887, 2001), Chen et al. (Vol. 279, No. 25, Issue of June 18, pp. 26058–26065, 2004), Pedersen et al. (Clin Exp Immunol, June 8 2004; 137:117–122), De Simoni et al. (American Journal of Pathology, Vol. 164, No. 5, May 2004, 1857-1863), Ambrus et al. (The Journal of Immunology, 2003, 170: 1374–1382), the alignments attached to the instant office action, Moller-Kristensen et al. (Journal of Immunological Methods 282 (2003) 159– 167) and Harlow et al. (Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, pp 44, 45 and 52) as applied to claims 1, 2, 4, 7, 8, 11 and 13 above and further in view of Carter et al. (6,407,213)(all cited on an IDS).
The teachings of Stahl in view of the knowledge in the art as evidenced by Collard… are given above.
However, these references do not explicitly teach the skilled artisan to inhibit MASP-2 dependent complement activation in a subject suffering from cerebral ischemia reperfusion injury or an acute ischemic stroke or a transient ischemic attack by administering a therapeutically effective amount of an anti-MASP-2 antibody having the properties of claims 1 / 8 and further having reduced effector function.
That said, the concept of manipulating the ability of a therapeutic antibody to fix complement by changing the antibody Fc isotype was well known in the art prior to applicant's date of invention as described by 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 IgGl, 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 IgG1. 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."
As would be obvious to one of ordinary skill in the art the goal of an inhibitory MASP-2 antibody is to inhibit the lectin complement pathway not kill cells bound by MASP-2. Thus, one of ordinary skill in the art would have been motivated to use, e.g., IgG2 as the Fc isotype for an anti-MASP-2 inhibitory antibody so as to minimize the possibility that binding of Clq to the anti-MASP-2 inhibitory antibodies would induce Clq-classical complement activation on the same cell surface to which the MBL:MASP-2:anti-MASP-2 antibody is bound. Such an occurrence would promote rather than inhibit the adverse effects of cerebral ischemia reperfusion injury.
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.
Claims 1-3, 5 and 7-13 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Larsen et al. (20070009528) in view of Stengaard-Pedersen et al. (N Engl J Med 2003;349:554-60) and Casanova et al. (JEM, Volume 199, Number 10, May 17, 2004 1295–1299) as evidenced by Moller-Kristensen et al. (Journal of Immunological Methods 282 (2003) 159– 167) (all cited on an IDS).
Larsen teaches a method of inhibiting MASP-2 dependent complement activation in a subject suffering from cerebral ischemia-reperfusion injury caused, e.g., by an acute myocardial infarction, or by a surgical procedure such as coronary artery bypass grafting, or by organ transplantation, or by ischemia-reperfusion injury associated with “major surgery,”
comprising administering to the subject, e.g., by intravenous or subcutaneous injection, a therapeutically effective amount of a monoclonal, recombinant or humanized antibody that specifically recognizes and binds an epitope within the C-terminal portion of MASP-2 with "significantly higher affinity than to any other molecule or part thereof." (see, e.g., Abstract, paragraphs 110, 116-121, 229, 238-239 and claim 110). Note that a cerebral ischemia/reperfusion injury caused by an acute myocardial infarction would be considered synonymous with an acute ischemic stroke by the ordinarily skilled artisan.
According to Larsen the anti-MASP-2 antibody can be administered by parenteral injection or infusion, e.g., via an intravenous, intramuscular or subcutaneous route (see paragraphs 229).
However, Larsen does not explicitly teach methods wherein the ischemia-reperfusion injury is associated with extremity or digit replantation (claim 10), or wherein the ischemia-reperfusion injury is associated with gastrointestinal ischemia-reperfusion (claim 12). Moreover, Larsen does not explicitly teach the methods of claim 4 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 polypeptide in the complement system (claim 4).
The ordinarily skilled artisan considering the teachings of Larsen would understand that “…preferred antibodies or functional equivalents thereof are capable of inhibiting C4 and/or C2 deposition in full serum to less than 50%, such as less than 40%, for example less than 30%, such as less than 25%, for example less than 20%, such as less than 15%, for example less than 10%, such as less than 5% of control C4 deposition. Preferably, the antibody is capable of inhibiting C4 deposition in full serum to less than 30%, preferably less than 25%, more preferably less than 20%, even more preferably less than 15%, yet more preferably less than 10%. Alternatively or in addition, preferred antibodies are capable of inhibiting C2 deposition in full serum to less than 30%, preferably less than 25%, more preferably less than 20%, even more preferably less than 15%, yet more preferably less than 10%.” (see paragraph 85).
Moreover, it would have been obvious to the skilled artisan contemplating inhibiting MASP-2 dependent complement activation in a subject suffering from cerebral ischemia reperfusion injury or an acute ischemic stroke or a transient ischemic attack by administering a therapeutically effective amount of a monoclonal antibody that binds an epitope within the C-terminal portion of MASP-2 with high affinity and specificity to administer an anti-MASP-2 antibody which is a potent antagonist of C4 and/or C2 deposition (consistent with Larsen paragraph 85) at a concentration capable of suppressing MASP-2 inhibitory activity as much as safely possible.
It would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have had a reasonable expectation of successfully doing so given the prior knowledge in the art as exemplified by Stengaard-Pedersen.
In particular, Stengaard-Pedersen teaches a patient with effectively no functional MASP-2 due to a homozygous asp120gly mutation in the CUB2 domain of his MASP-2 (see first para. results on page 555) also exhibits severe hypocomplementemia including anti-C1q autoantibodies, low C1q levels and an alternative pathway defect (see 2 page Supplementary Appendix 1 from Stengaard-Pedersen).
However, first order relatives of this patient who were heterozygous for the same CUB2
mutation and who had mannan binding lectin complement activity at or below the 5th percentile
(see pages 557 and 559, left col., 1st full paragraphs of each) were not reported to be predisposed
to infection or to exhibit hypocomplementemia. It is difficult to believe that Stengaard-Pedersen would not have investigated the possibility of infection or hypocomplementemia in these heterozygous patients and reported upon it if present.
Moreover, the teachings of Stengaard-Pedersen are consistent with other knowledge in the art of MBL deficiency as exemplified by Casanova – MBL deficiency is both common and not a major risk factor for infectious diseases in adults (see page 1295-6 bridging paragraph – page 1296 col. bridging paragraph and “Conclusion” at page 1298) – consistent with the notion that it would have been obvious to the skilled artisan to suppress MASP-2 inhibitory activity far greater than 50% when treating cerebral ischemia reperfusion injury or an acute ischemic stroke or a transient ischemic attack with a MASP-2 inhibitory monoclonal antibody.
With respect to using a MASP-2 antibody that selectively inhibits MASP-2 dependent complement activation without substantially inhibiting C1q-dependent complement activation, given the structurally similarities between MASP-2 and a number of other complement proteins – MASP-1, MASP-3, C1r and C1s (see attached alignments) – it would have been a particular concern to the ordinarily skilled artisan making a MASP-2 inhibitory antibody that the antibody bind with high affinity and specificity to MASP-2.
One reason the skilled artisan would have been motivated to prepare such an antibody is to avoid unwanted binding to the C1r/C1s proteases of the classical complement pathway thereby not interfering with the protective role of these proteins in fighting diverse pathogens.
Yet another reason the skilled artisan would have been motivated to avoid cross-reactivity with, e.g., MASP-1/MASP-3, is because MASP-2 was known to be one of the least abundant complement proteins in serum as described in the instant specification at page 244, 1st full paragraph and as evidenced by Moller-Kristensen at Fig. 3. Thus, cross-reactivity with MASP-1/MASP-3 would be expected to merely dilute the desired inhibitory effect on MASP-2. When the above is taken together, it would have been obvious to one of ordinary skill in the art to make and use an inhibitory anti-MASP2 antibody having high MASP-2 affinity and specificity.
Moreover, 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.
Thus, the skilled artisan would have been motivated to inhibit MASP-2 dependent complement activation in a subject that has recently had or is having cerebral ischemia reperfusion injury / acute ischemic stroke with an anti-MASP-2 antibody that selectively inhibits MASP-2 dependent complement activation without substantially inhibiting C1q-dependent complement activation and further with an anti-MASP-2 antibody that binds SEQ ID NO: 6 with an affinity of at least 10 times greater than it binds to a different polypeptide in the complement system.
As to the method of claim 10 involving ischemia-reperfusion injury is associated with extremity or digit replantation, even if not explicitly taught by Larsen, one of ordinary skill in the art would have immediately envisaged such an embodiment given that digit replantation is the most common form of extremity transplantation. As to the method of claim 12, since ischemia-reperfusion injury is well-known to be associated with colon resection for the treatment of ulcerative colitis, it further would have been obvious to one of ordinary skill in the art to treat such ischemia-reperfusion injury by administering an anti-MASP-2 antibody consistent with the teachings of Larsen.
In conclusion, 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.
Claims 4 and 6 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Larsen et al. (20070009528) in view of Stengaard-Pedersen et al. (N Engl J Med 2003;349:554-60) and Casanova et al. (JEM, Volume 199, Number 10, May 17, 2004 1295–1299) as applied to claims 1-3, 5 and 7-13 above and further in view of Carter et al. (6,407,213) as evidenced by the attached alignments, Moller-Kristensen et al. (Journal of Immunological Methods 282 (2003) 159– 167) and Harlow et al. (Using Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1999, pp 44, 45 and 52) (all cited on an IDS).
That said, when making an anti-MASP-2 inhibitory antibody that binds the C-terminal portion of MASP-2 as directed by Larsen, it would have been a particular concern to the ordinarily skilled artisan that the MASP-2 inhibitory antibody bind with high affinity and specificity to MASP-2 in view of the strong structurally similarities between MASP-2 and a number of other complement proteins – MASP-1, MASP-3, C1r and C1s (see attached alignments).
One reason the skilled artisan would have been motivated to prepare such an antibody is to avoid unwanted binding to the C1r/C1s proteases of the classical complement pathway thereby not interfering with the protective role of these proteins in fighting diverse pathogens. Yet another reason the skilled artisan would have been motivated to avoid cross-reactivity with, e.g., MASP-1/MASP-3, is because MASP-2 was known to be one of the least abundant complement proteins in serum as described in the instant specification at page 244, 1st paragraph and as evidenced by Moller-Kristensen at Fig. 3. Thus, cross-reactivity with MASP-1/MASP-3 would be expected to merely dilute the desired inhibitory effect on MASP-2. When the above is taken together, it would have been obvious to one of ordinary skill in the art to make and use an inhibitory anti-MASP2 antibody having high MASP-2 affinity and specificity, consistent with the requirement of instant claim 4.
Moreover, 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.
As to practicing the claimed method of treatment with an anti-MASP-2 antibody with
reduced effector function, the concept of manipulating the ability of a therapeutic antibody to fix
complement by changing the antibody Fc isotype was well known in the art prior to applicant's
date of invention as described by 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 IgGl, 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 IgG1. 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."
As would be obvious to one of ordinary skill in the art there is no apparent advantage to making a MASP-2 inhibitory antibody that can activate complement or activate ADCC because the goal of an inhibitory MASP-2 antibody is to inhibit the lectin complement pathway not kill cells bound by MASP-2. Indeed, one of ordinary skill in the art would have been motivated to use, e.g., IgG2 as the Fc isotype for an anti-MASP-2 inhibitory antibody so as to minimize the possibility that binding of Clq to the anti-MASP-2 inhibitory antibodies would induce Clq-classical complement activation on the same cell surface to which the MBL:MASP-2:anti-MASP-2 antibody is bound. Such an occurrence would promote rather than inhibit the adverse effects of ischemia reperfusion injury in a allogeneic heart transplant patient.
With respect to administering the MASP-2 inhibitory antibody immediately after to about 24 hours from the onset of the acute ischemic stroke, it would have been obvious to one of ordinary skill in the art to do so because as soon as an episode of ischemia and reperfusion it imminent or has occurred one would wish to immediately protect against lectin complement pathway mediated injury.
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