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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
This action is in response to claim amendments filed 5/18/26. Claims 1-6, 11-12, 17-19, 23, and 27-32 are pending and under examination.
Withdrawn Rejections
The rejection under §112(b) is withdrawn in light of the amendments.
The rejection under §112(d) is withdrawn because claim 76 was canceled.
The rejection under §112(a) is withdrawn because claim 76 was canceled.
The rejection under §101 is withdrawn because claim 65 was canceled.
The rejection under §102 is withdrawn because claim 65 was canceled.
Maintained Rejections and New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
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 1-6, 11-12, 17-19, 23 and 27-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yednock (US 20170152309) in view of Muizelaar (IDS 11/28/23 citation CO) and further in view of Hammad (IDS 11/28/23 citation CF), McGonigal (previously cited), and ScienceDaily (IDS 11/28/23 citation CA).
Regarding claim 1, Yednock teaches an antibody Fab fragment that binds to C1q (claim 1). Yednock teaches using an anti-C1q antibody to inhibit synapse loss, specifically excessive synapse loss. Further, Yednock teaches many specific examples of this (paragraphs 37-38), including specific neurodegenerative diseases associated with the loss of synapses or nerve connections (paragraph 37; claims 1, 31, 32, and 37) and ischemia-reperfusion injury (paragraph 38; 48; 101). In particular, Yednock notes that the complement factor is rapidly induced by “a variety of insults to the brain such as infection, ischaemia, and injury” (paragraph 164).
Yednock does not explicitly disclose TBI. The antibody of Yednock is a Fab, which is not a full-length antibody.
With respect to TBI, Yednock does not explicitly disclose TBI. However, Yednock does note the relevance of the inappropriate activation of the complement system in ischemia-reperfusion injury (paragraph 2). Further, Yednock teaches the anti-C1q therapy as treating “brain injury” (paragraph 9) as well as the increase of C1q after brain injury (paragraph 97).
Muizelaar teaches that traumatic brain injury is a brain injury (severe head injury). Muizelaar also teaches that TBI is an ischemia-reperfusion-type injury (title).
Hammad also teaches TBI is a brain injury: “TBI is defined as damage to the brain resulting from an external force that causes the brain to move quickly within the skull” (p.1 C1). Hammad also teaches the complement system plays a role in the inflammatory reaction, which is a primary contributor to the injury in TBI (abstract). Specifically, Hammad teaches that microglia exist in either the M1 state—which damages healthy cells—or the M2 state—which is associated with improved cellular survival and tissue repair—and that C1q “contributes to a shift towards the M1 phenotype” (p.2 C1).
One of ordinary skill in the art at the time of filing would have found it obvious to utilize the method of Yednock (administering anti-C1q antibody to treat brain injury) to treat TBI. TBI is a brain injury characterized by ischemia-reperfusion and deleterious activation of the complement system, while the method of Yednock is one of treating brain injury, in particular ischemia-reperfusion injuries and those which would benefit from inhibited C1q. Thus, while not explicitly naming TBI as the “brain injury”, one would have had a reasonable expectation of success in using Yednock’s method to treat TBI because Yednock teaches the method treats brain injury as well as pathologies present in TBI. This is further reinforced by Yednock’s discussion of the relevance of the complement system to ischemic injuries, while Muizelaar teaches that TBI is such an ischemic event and Hammad teaches the relevance of the complement system in TBI.
With respect to a “full-length antibody”, Yednock teaches using an antibody fragment, specifically a Fab. However, Yednock teaches throughout the document that the therapeutic mechanism of this Fab is that the antibody fragment binds and inhibits C1q, inhibiting the classical complement system (paragraphs 6; 32; 96).
McGonigal teaches the antibody M1, which binds and neutralizes C1q (p.3 C1). McGonigal teaches the M1 antibody was compared against a “non-specific isotype control IgG1 mAb”; since the isotype is defined by the Fc region, the M1 antibody is a full-length antibody. McGonigal tests the antibody in a mouse model for axonal injury as a result of inflammation mediated by the complement system (abstract). McGonigal demonstrates that the anti-C1q antibody M1 “attenuates [neuron] injury with a consequent neuroprotective effect” (abstract).
It would have been obvious at the time of filing that the anti-C1q antibody Fab of Yednock could be substituted with the anti-C1q antibody of McGonigal with predictable results. Both antibodies target and inhibit C1q, both documents describe the therapeutic benefits of inhibiting the classical complement pathway, and both documents describe the neuroprotective effect of these antibodies. Further, Yednock explicitly states that the antibody should bind the same C1q epitope as the M1 antibody (claim 7), which is the antibody of McGonigal, and suggests the Fab of Yednock has the identical CDRs (binding regions) of the M1 antibody (paragraph 24) and refers to the Fab as “M1 Fab” (paragraph 56), further providing a reasonable expectation that using the M1 antibody would achieve the same effects as Yednock since the antibody of Yednock is the McGonigal M1 antibody in a Fab format.
In summary, one of ordinary skill in the art would have known that the classical complement pathway can damage neurons (Hammad and Muizelaar) and that inhibiting the classical complement pathway by inhibiting specifically C1q is a desirable therapeutic outcome to protect neurons from such damage (Yednock and McGonigal). One of ordinary skill in the art would further have known that TBI is characterized by ischemia/reperfusion, leading to activation of the classical complement pathway which plays a role in the damage caused by TBI (Hammad and Muizelaar). One would have known that using an anti-C1q antibody is therapeutic for treating such ischemia- and complement-related conditions such as TBI (Yednock) and would have expected similar results using an antibody which demonstrates similar inhibition and neuroprotective properties (McGonigal), particularly as the antibody of Yednock is the Fab region of McGonigal’s M1 antibody, having the same CDRs and binding the same C1q epitope. Thus, the method of claim 1 as a whole would have been obvious.
Regarding claims 2-5, Yednock does not explicitly disclose treatment within the time frames claimed, i.e., a range of within the first 4 weeks of a brain injury to within six hours of a brain injury. However, “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP §2144.05(II). “[I]t is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions” (MPEP §2144.05(II)(A)).
Such is the case here. Where the only difference between the prior art and the instant claim is in an explicit timing requirement which represents no more than optimization of the prior art drug timing, such optimization would have been obvious. Further, as taught by ScienceDaily, “harmful changes to the brain’s synaptic connections occur within the first three minutes following a stroke” (title; summary) and indicates that while stroke can be treated “three hours after onset”, damage is occurring “almost immediately”. Thus, one of ordinary skill in the art at the time of filing would have found it obvious to administer treatment as soon after the injury as possible to limit the damage, making treatment within four weeks of the injury obvious. The same applies to “within six hours after [the TBI]”, as ScienceDaily teaches the damaging effects occur within minutes and suggests treatment should commence within three hours.
Regarding claim 6, inhibition of synapse loss is one means by which the treatment functions according to Yednock; see e.g., paragraphs 9, 166. Further, as the antibody of McGonigal inhibits the same target (C1q), is the parent antibody of the Yednock M1 Fab, and is also neuroprotective, these same results would be expected when using the M1 antibody.
Regarding claim 11, Yednock teaches these functions of the antibody (paragraph 31). Moreover, administering the same agent (anti-C1q antibody) to the same subject (one with a brain injury/synapse loss) must achieve the same results absent evidence to the contrary. McGonigal also teaches this result, teaching that anti-ganglioside antibodies pathogenically target nerve cells (p.2 C1; i.e., autoantibody) and that the M1 antibody prevents C1q from binding the anti-ganglioside antibody (autoantibody; p.3 C1). Yednock teaches the M1Fab has the same properties as the M1 antibody (paragraphs 22-24; figures 1 and 2).
Regarding claim 12, as above, administering the same agent (anti-C1q antibody) to the same subject (one with TBI/synapse loss) must achieve the same results.
Regarding claim 17, as above, administering the same agent (anti-C1q antibody) to the same subject (one with TBI/synapse loss) must achieve the same results. Further, Yednock teaches this is one of the mechanisms by which the method functions (paragraph 9: “neutralizing the activity of complement factors such as C1q”) as does McGonigal (p.3: “neutralizes C1q and thereby prevents binding”).
Regarding claim 18, see rejection of claim 11; for example, paragraph 31 of Yednock teaches the disruption of C1q binding to an autoantibody and C1q binding to C1r while McGonigal also teaches the antibody prevents C1q binding anti-ganglioside antibodies. Yednock teaches the M1 Fab has the same properties as the M1 antibody as discussed above.
Regarding claim 19, Yednock discloses the inhibition of the same biological activities, e.g., synapse loss (paragraph 32) while McGonigal teaches the antibody prevents activation of the classical complement cascade, i.e., activation pathway (p.3 C1).
Regarding claim 23, McGonigal teaches the antibody is monoclonal (p.3 C1: “monoclonal antibody M1”).
Regarding claim 27, Yednock teaches the antibody has a light chain of SEQ ID NO: 2. This sequence comprises SEQ ID NOs: 5, 6, and 7 within the HVR (CDR) of the chain. McGonigal does not disclose the CDRs of M1. However, there is ample evidence that the M1 antibody also comprises these claimed sequences. First, the sequence of M1 is inherent; whether others in the art knew the sequence or not at the time of filing, the M1 antibody necessarily had a sequence of amino acids. Second, as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). In the same way, the Office is not equipped to obtain and sequence the M1 antibody to determine the variable domain sequences.
Nevertheless, Yednock teaches the M1 Fab is the Fab portion of the M1 antibody; Yednock teaches the Fab has the identical CDRs (binding regions) of the M1 antibody (paragraph 24) and refers to the Fab as “M1 Fab” (paragraph 56). Having the identical CDRs as M1 is sufficient evidence to conclude that the McGonigal antibody—which is M1—must have CDRs of instant SEQ ID NOs: 5-7 as taught by Yednock.
Regarding claim 28, the above reasoning is also true for the heavy chain. Yednock teaches the antibody has a heavy chain of SEQ ID NO: 1. This sequence comprises SEQ ID NOs: 9, 10, and 11 within the HVR (CDR) of the chain and, as Yednock teaches these are the same for antibody M1, the McGonigal antibody (M1) must also have these sequences.
Regarding claims 29 and 30, Yednock SEQ ID NO: 2 comprises a sequence 100% identical to instant SEQ ID NO: 37 as depicted below:
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A Fab includes the heavy and light chain variable regions of a full-length antibody (Yednock paragraphs 59-60). Thus, as above, the evidence suggests that the M1 Fab comprises the same VH and VL as M1, which supports the conclusion that M1 also comprises instant SEQ ID NO: 37.
Regarding claims 31 and 32, Yednock SEQ ID NO: 1 comprises a sequence 100% identical to instant SEQ ID NO: 33 as depicted below:
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For the same reasons above, M1 comprises instant SEQ ID NO: 33.
Therefore, claims 1-6, 11-12, 17-19, 23, and 27-32 would have been obvious.
Double Patenting
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10723788 in view of Muizelaar and further in view of Hammad, McGonigal, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to an antibody with the same VH/VL regions as the instant antibody (claims 30 and 32), differing only in the instant antibody being a full-length antibody while the reference antibody is a Fab. However, McGonigal teaches the M1 antibody achieves the same results and inhibits the same target as that of the reference Fab, making substituting the monoclonal full-length antibody of McGonigal a predictable substitution. The reference document also claims a kit with the antibody and the written instructions (claim 7). There are no method claims in the reference patent. See the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office’s use of disclosed utilities of compositions when applying double patenting rejections to method claims. The utility disclosed in ‘788 for these antibodies is both in treatment of synapse loss as well as determining risk for such (see discussion of ‘309 above, which is the PgPub of the reference patent).
Given this utility, it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, McGonigal, and ScienceDaily as discussed above and incorporated herein.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11999779 in view of Muizelaar and further in view of Hammad, McGonigal, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to inhibiting synapse loss using an antibody (SEQ ID NOs: 1 and 2) with the same claimed functions. Thus, the reference claimed antibody differs from the instant antibody only in the instant antibody being a full-length antibody while the reference antibody is a Fab. However, McGonigal teaches the M1 antibody achieves the same results and inhibits the same target as that of the reference Fab, making substituting the monoclonal full-length antibody of McGonigal a predictable substitution. Given the reference claims a method of treating any C1q mediated disease where the classical complement pathway is activated (claim 6), inflammatory disease (claim 13) and inhibiting synapse loss (claim 1), it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, McGonigal, and ScienceDaily as discussed above and incorporated herein.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9708394 in view of Muizelaar and further in view of Hammad, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to a full-length antibody meeting the criteria of the most specific anti-C1q antibodies of the instant claims (see reference claims 1(b), 2, 3). The instant methods are not claimed in the reference patent. However, see the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office’s use of disclosed utilities of compositions when applying double patenting rejections to method claims. The utility disclosed in ‘394 for these antibodies is both in treatment of synapse loss as well as determining risk for such (see e.g., C34, C55). Given this utility, it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, and ScienceDaily as discussed above and incorporated herein.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10227398 in view of Muizelaar and further in view of Hammad, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to inhibiting synapse loss using a full-length antibody (SEQ ID NOs: 1 and 2) with the same claimed functions, meeting the criteria of the most specific anti-C1q antibodies of the instant claims (claims 30 and 32). Given the reference claims a method of treating any C1q mediated disease where the classical complement pathway is activated (claim 6), inflammatory disease (claim 13) and inhibiting synapse loss (claim 1), it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, and ScienceDaily as discussed above and incorporated herein.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10590190 in view of Muizelaar and further in view of Hammad, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to a full-length antibody meeting the criteria of the most specific anti-C1q antibodies of the instant claims (claims 30 and 32; see reference claims 1(b), 2, 3). The instant methods are not claimed in the reference patent. However, see the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office’s use of disclosed utilities of compositions when applying double patenting rejections to method claims. The utility disclosed in ‘394 for these antibodies is both in treatment of synapse loss as well as determining risk for such (see e.g., C34, C55). Given this utility, it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, and ScienceDaily as discussed above and incorporated herein.
Claims 1-6, 11-12, 17-19, 23, and 27-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10316081 in view of Muizelaar and further in view of Hammad, and ScienceDaily. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims are directed to an antibody meeting the criteria of the most specific anti-C1q antibodies of the instant claims (claims 30 and 32; see reference claims 1(b), 2, 3). The instant methods are not claimed in the reference patent. However, see the decisions in Sun Pharmaceuticals v Eli Lily Fed Cir July 28, 2010; Geneva v GlaxoSmithKline 349, F.3d 1373; and Pfizer v Teva 518 F3d 1353 supporting the Office’s use of disclosed utilities of compositions when applying double patenting rejections to method claims. The utility disclosed in ‘394 for these antibodies is both in treatment of synapse loss as well as determining risk for such (see e.g., C34, C55). Given this utility, it would have been obvious that the full-length version of the reference antibody could be predictably used to treat TBI within 6 hours based on the teachings of Muizelaar, Hammad, and ScienceDaily as discussed above and incorporated herein.
Response to Arguments
Applicant's arguments filed 5/18/26 have been fully considered but they are not persuasive.
Applicant argues Yednock alone does not teach the claimed method (p.7-8). In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that because the rejection relies on modifications to Yednock, where Yednock does not itself teach these modifications, that the combination is driven by hindsight; at p. 7 Applicant refers to this as impermissible hindsight. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Further, if the proposed modifications to Yednock were disclosed in Yednock, there would have been no need for additional references. Applicant is essentially arguing that a claim must be anticipated under §102 or else impermissible hindsight was used. This is not persuasive because it is contradictory to the statutes under e.g., 35 USC §103.
Applicant argues the conditions disclosed in Yednock are not TBI. This is true but does not point to any specific deficiency in the rejection which clearly articulated why TBI would have been obvious.
Applicant argues that Yednock does not “discuss the distinctive pathophysiology of TBI” (p.8). While Yednock does not attribute specific pathophysiology to TBI as stated in the rejection, Yednock extensively discusses, e.g., inhibiting loss of synapses or nerve connections, treating diseases associated with complement activation, and ischemia-reperfusion. These teachings, combined with the teachings of the other references, would have made obvious treatment of TBI with a reasonable expectation of success as articulated in the rejection.
Applicant argues that the difference between TBI and the conditions of Yednock is mechanistic. Applicant argues other factors of TBI that are not shared by every disease disclosed by Yednock. This does not point to any specific deficiency in the reasoning applied by the Examiner.
Applicant makes the conclusory statement that “a person of ordinary skill in the art would not have assumed that a therapeutic strategy proposed for synapse loss in chronic neurodegenerative diseases or for other non-traumatic insults would predictably treat TBI”. Applicant is reminded that “arguments of counsel cannot take the place of factually supported objective evidence" (MPEP§2415). Yednock explicitly discloses the mechanism by which the C1q antibody functions as well as the pathophysiology being treated. The art of record establishes that these same mechanisms and pathophysiology are shared in TBI, particularly in light of Yednock’s teaching that the therapy applies to ischemia-reperfusion injury. Applicant’s mere assertion that one would not have found it predictable does not point to any objective evidence or reasoning to support this conclusion and does not specifically point out any deficiency in the reasoning of record establishing why there was a reasonable expectation of success.
Applicant argues Yednock provides no data, no mechanistic explanation, and no express suggestion that C1q inhibition would be beneficial after traumatic mechanical injury. This is not persuasive because it does not address the rejection as a whole nor does it explain why the teachings of Yednock regarding, e.g., the mechanism, would not have been expected to apply to TBI.
Applicant argues the modification to include a full-length antibody comes from “a different reference involving a different disease model”. This is not persuasive. A rejection under §103 allows for the use of multiple references, so the argument that a “different reference” was combined with Yednock and so the rejection must be hindsight is, on its face, not persuasive. Further, Applicant does not explain how the use of a different disease model would have altered the expectations of the person of ordinary skill in the art as to how the antibody functions. Yednock clearly establishes the Fab as therapeutic by inhibiting C1Q; McGonigal teaches M1 also inhibits C1q and so one of ordinary skill in the art would have expected similar results. It is further pointed out that Yednock explicitly teaches the Fab should bind the same C1q epitope as the M1 antibody of McGonigal. This further undermines Applicant’s mere suggestion that the combination is driven entirely by impermissible hindsight.
Applicant presents arguments as to what Muizelaar does not teach (p.9). As above, a piecemeal analysis of a rejection relying on multiple references is not persuasive. Muizelaar was not relied upon for teaching C1q, C1q antibodies, or the classical complement pathway and so an argument that Muizelaar does not teach these things is not persuasive.
Applicant argues Muizelaar suggests oxygen radical scavenging “not complement inhibition” may be therapeutically useful. To be clear, as Applicant also argues, Muizelaar is silent regarding complement inhibition. Muizelaar teaching a different treatment may be therapeutic does not in any way undermine the teachings of Yednock that C1q inhibition would be therapeutic for ischemia-reperfusion injuries, where Muizelaar establishes TBI is such an injury. As such, Applicant’s argument that Muizelaar “points away” (teaches away) from C1q is wholly unpersuasive. A true “teaching away" from a concept must be explicit, not just an otherwise general suggestion. Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Applicant argues that the “partial overlap” of mechanism is not a teaching or suggestion in the art. First, obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Applicant’s argument that there is no specific suggestion or teaching in the art is therefore unpersuasive because it does not argue against the rationale set forth in the rejection. Further, Applicant fails to elaborate on how this admitted overlap of mechanisms would arrive at a conclusion that the treatment of Yednock would not function to treat TBI, which is an ischemia-reperfusion type injury and where TBI—even if not identical to other diseases—shares the inflammation/complement activation mechanisms taught by Yednock as well as the established understanding of C1q in the inflammatory reaction as taught by Hammad.
Applicant argues Hammad also teaches away from the proposed therapeutic benefit of C1q (p.9-11). Applicant argues Hammad teaches that complement may have both harmful and beneficial effects and that this “cautionary teaching” would have discouraged a skilled artisan from broadly inhibiting C1q “without further evidence”. Again, as throughout the arguments, Applicant selects a single teaching and argues the teaching in a vacuum. The obviousness (35 USC §103) rejection must be considered as a whole, e.g., considering the combination of teachings, not just a single, isolated teaching. The “further evidence” suggested by Applicant comes from the direct teachings set forth in the rejection, such as Yednock explaining the mechanism of C1q, the therapeutic benefits in treating ischemia-reperfusion, that TBI is an ischemia reperfusion injury, and that inhibiting C1q treats an inflammatory response. Notably, Applicant is attempting to argue that because the multiple members of the complement system may have harmful or beneficial effects that specifically C1q was unpredictable.
Applicant argues that Hammond teaches mice lacking C1q are more susceptible to bacterial infection and a greater incidence of epileptogenesis, which are a particularly serious concern in TBI patients, citing Hammad at page 4. This is not persuasive because this is not supported by Hammad. Hammad does teach that mice lacking either C1q or C3 are more susceptible to S.pnemoniae infections in a model of pneumococcal meningitis (p.4 C2). Applicant does not explain how a model of meningitis is an art accepted model of TBI or of ischemia-reperfusion. Further, even if accepted as relevant to TBI, Hammad does not state that these are a “particularly serious concern” as alleged by Applicant. Hammad does teach that C1q knockout mice have a greater incidence of epileptogenesis. Hammad does not state that this is a particular concern for treating TBI nor does Hammad (or any art of record) indicate that acute treatment with a C1q inhibitor is expected to create the same higher incidence of a genetic knockout.
Taken as a whole, none of these alleged teachings are a direct criticism of using C1q inhibition to treat TBI, which is required for a true teaching away. In other words, the method as arrived at by the combination in the prior art would provide a reasonable expectation of treating TBI—as instantly claimed—and a higher risk of infection or epileptogenesis does not undermine this expectation, particularly as such a result is not claimed. Within the BRI of the instant claims, treatment is reducing the symptoms, signs, or pathology “of a subject’s condition” (instant specification p.60), that condition being TBI. This broad definition of “treat” does not exclude, e.g., an increased risk of developing an infection. A “risk” of infection, even if elevated, is not part of the etiology of TBI (the condition) nor is it indicative that the subject’s condition would not improve or that the subject’s condition would not worsen as much as if the subject did not receive treatment at all (instant specification p.70).
Applicant is correct that Hammad teaches the complement system plays a role in neurogenesis and in some cases has a neuroprotective effect. However, this does not support Applicant’s argument that these teachings are “completely at odds” with the Office’s rationale. Applicant argues that the teachings of Hammad arrive at the conclusion that “complement biology” (Applicant does not specify C1q) was “unresolved, context-dependent, and potentially dangerous” (p.10). Considering the teachings of Hammad alone is insufficient to arrive at a conclusion that Hammad teaches away from the proposed solution in Yednock because the results are not unpredictable as Applicant asserts. Hammad teaches that 7 days after an insult in a C3 null mouse, there was reduced neurogenesis. As above, this is not representative of a system of inhibition but rather a genetic knockout. Further, to the extent Applicant argues that knockouts are an art recognized model, this is a model of complete complement inhibition, not partial as suggested by the combined references. During the prosecution of this situation in parent application 16/671920, which also utilized the combination of Yednock/Hammad, Applicant provided a figure on page 7 of the appeal brief mailed 2/21/23; that figure is reproduced here:
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Referring to this figure, the art suggests inhibiting C1q, which would still allow for partial function of the complement system by way of the lectin pathway and alternative pathway. Such partial inhibition is taught as beneficial when treating ischemic injuries, of which TBI is an ischemic injury (see rejection). In contrast, Applicant’s argument rests on undermining these teachings by demonstrating that blocking the entire system (the C3 knockout) is detrimental. As apparent from the figure, inhibiting C3 would block not only the classical pathway (as in a C1q inhibition) but also both the lectin and alternative pathways. Thus, this is not considered a fair analogy to the partial inhibition suggested by the combination of the prior art particularly because the art recognizes this result as stemming from inhibition of the pathway as a whole, not just a part. Hammad attributes this reduced neurogenesis to inhibition of C3aR: “administration of a C3aR antagonist to mice results in reduced neurogenesis”. This is a downstream member of the complement pathway which is affected by several systems such as lectin and the alternative pathway. Inhibiting this downstream “choke point” or eliminating it entirely (C3 knockouts) will predictably lead to more extreme effects as it is effectively cutting off multiple systems, not just the C1q portion. Thus, rather than a teaching away, Hammad is better viewed as a teaching that the entirety of the complement system should not be prevented from function via, e.g., a C3 knock out. This is in line with the teachings that there is neuroprotective element to the system as a whole. What is lacking in Applicant’s argument is that Hammad never criticizes inhibiting C1q specifically, while Yednock teaches the beneficial results of doing so.
To this point, Hammad explicitly teaches:
“activation of the complement system can have a number of deleterious effects in the CNS” (p.7 C1)
“C1q contributes to a shift towards the M1 phenotype”, where “M1 microglia can also result in damage to healthy cells” (p.2 C1)
“There is a bias towards M1 over M2 in TBI secondary injury” (p.2 C1)
The M1 phenotype damages healthy cells
The M2 phenotype is associated with improved cellular survival and tissue repair
“When the CNS is subjected to an insult that results in injury, a cascade of secondary pathophysiological events is induced, a key part of which is a prominent neuroinflammatory response. These secondary events compromise the integrity of the neurons” (p.5 C1)
“The complement system appears to play a particularly significant role in the secondary injury that occurs in the context of TBI” (p.5 C2)
On the whole, it is agreed that when viewing the complement system in its entirety, there are detrimental and beneficial effects of the system. However, the rejection does not attempt to argue that inhibiting the entire complement system is beneficial. Rather, all of the cited art agrees that the complement system is detrimental in ischemia-reperfusion injuries—including TBI—and that specifically inhibiting C1q is recognized as an effective treatment for this, in part by shifting microglia from their damaging phenotype (M1) to their M2 phenotype. Thus, Applicant’s argument that the prior art teaches unpredictability in certain contexts is not persuasive because the prior art teaches when and how the complement system is either beneficial or detrimental and teaches a specific means of inhibiting a specific portion of that system in order to elicit beneficial results.
In summary, Hammad teaches there are some instances where the complement system should not be wholly inhibited and that genetic knockout of C1q can lead to increased risk of certain infections or of epileptogenesis. Hammad does not teach that these increased risks warrant the avoiding of treatment of TBI nor provide any reason to expect that the method of Yednock would not treat TBI within the meaning of the terms in the instant claim. Moreover, this “helps-and-harms” system was known and the art of record, taken as a whole rather than analyzed in isolation, provides a reasonable expectation of success when applying C1q inhibition to treat TBI as articulated in the rejection.
Applicant argues that Hammad teaches the complement system should be manipulated, not inhibited. Nowhere does Hammad teach that “manipulated” excludes inhibition. Rather, inhibition of the complement system is clearly within an ordinary understanding of “manipulate”. Further, the use of “manipulate” is used by Hammad solely in the section titled “Future perspectives”. In other words, Hammad is now opining about potentials and possible directions for research, none of which is objective evidence undermining any of the statements made previously by Hammad. Hammad states “if there is indeed evidence for a neuroprotective role of complement in TBI”, clearly indicating that no such evidence was objectively set forth prior to that statement (“if”). This is in contrast to the objectively deleterious effects of the complement system in TBI as well as the teachings of anti-C1q treatment being effective to treat ischemia-reperfusion injury, TBI being known in the art as one such species within that genus as articulated by the rejection. Thus, based on the combination of references, one would have found it obvious to manipulate (Hammad) by inhibiting (Yednock) C1q.
Applicant’s argument that Hammad’s proposed direction is materially different from the claimed method. This does not point to any specific deficiency in the rejection. Providing an alternative is not a “teaching away” from a proposed solution.
Applicant argues that Hammad does not teach inhibiting the classical complement pathway to prevent post-traumatic cognitive functions; this result is not claimed. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that Hammad is a teaching away because it suggests that the path taken by Applicant is unlikely to be productive of the desired result. The desired result it “treating TBI” and, as Applicant points out, Hammad does not teach inhibiting C1q to treat TBI and so cannot be seen to discredit that approach. Hammad generally describes that, while multifaceted, the complement system behaves differently when different parts are inhibited and further teaches the results of inhibiting those particular parts. Nothing in Hammad undercuts inhibition of C1q in TBI nor does it conflict with the explicit teachings of inhibiting specifically C1q for treatment of ischemia as in Yednock. Applicant’s argument that increased infection or a broad assertion that sometimes the complement system is beneficial does not criticize or discourage from the proposed course of action.
Applicant argues that the question of inhibiting C1q is “unresolved” (p.11). Taken on its face, this is clear that Hammad is not teaching away, which requires the art to criticize, discredit, or otherwise discourage the solution claimed….”; a statement that the course of action lacks absolute predictability is not such a statement. Further, while Hammad teaches certain potential downsides to inhibiting C1q (via genetic knockout), Hammad also teaches the role of complement specifically in TBI where inhibition treats TBI (p.6) rather than a teaching that some other condition might be increased. Hammad teaches inhibiting the classical and lectin complement pathway in TBI leads to reduced damage (p.6 C2) and that C1q specifically contributes to microglia adopting a damaging phenotype, clearly suggesting that inhibiting C1q would reduce this shift. Hammad teaches that C1q results in synapse loss (p.5 C1), corroborating Yednock’s teaching that inhibiting C1Qq will reduce synapse loss. While Applicant is correct that C1q genetic knockout mice have increased incidence of epileptogenesis, this teaching is directly after the teaching that these same mice “possessed excess synapses and showed reduced synaptic pruning”. Clearly, in a condition where synaptic loss is to be deterred such as in TBI, the person of ordinary skill in the art would have had a reasonable expectation that preserving existing synapses according to Yednock would treat TBI within the meaning of the term in the claim, irrespective of whether or not this results in increased incidence of epileptogenesis. However, it is noted that having excess synapses due to a lifelong lack of C1q (resulting in increased epileptogenesis) is not commensurate with treating a condition where synapses are in danger of being lost, though this does provide additional reasoning to expect such a treatment to be beneficial.
Applicant argues that “Guillian-Barre syndrome is not TBI”. Applicant argues the differences between GBS and TBI from a pathogenesis stance. Applicant then extends these differences to a conclusion that a full-length antibody would not treat TBI. This is not persuasive. None of Applicant’s arguments indicate why the full-length antibody would not be expected to elicit similar results as the Fab in Yednock, particularly as they are taught as binding the same epitope. McGonigal is not relied on for a teaching that C1q inhibition would treat TBI, though a demonstration that M1 is also therapeutic provides additional reasonable expectation that M1 could be used in another therapeutic context, such as treating TBI. While Applicant again argues impermissible hindsight, Applicant does not point to any fact derived solely from Applicant’s disclosure and not the prior art. While McGonigal may not provide “data or rationale” for C1q inhibiting trauma-induced cognitive deficits, McGonigal is not required to teach each and every aspect of the claim alone where the rejection is based on a combination of references.
Applicant argues the inclusion of ScienceDaily because ScienceDaily does not mention TBI but rather is directed to stroke. Applicant agrees, however, that “stroke is a vascular even caused by loss of blood flow to the brain” (remarks 5/18/26 p.12), where such loss of blood flow is part of the pathology of TBI (ischemia). Further, Applicant makes no argument as to why, when a person of ordinary skill in the art was faced with a patient having TBI and possessed the method by which to treat it, that this person would not find it obvious to treat the subject immediately as discussed in the rejection. See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396. Applicant argues that the fact that neurological injury may progress quickly is “unremarkable”. The Examiner agrees that this fact is generally accepted and was known; however, the rejection was required to address this unremarkable timing because it was claimed, in part by providing ScienceDirect to establish that brain injury occurs quickly and to provide a motivation for the person of ordinary skill in the art to begin treatment as soon as possible, including “within 6 hours” of the TBI.
Applicant’s arguments spanning p. 12-13 essentially repeat the above arguments and suggest that this amounts to a lack of motivation to combine. This is not persuasive for the above reasons as well as those in the rejection. Further, Applicant’s arguments appear to suggest that the rejection requires selecting certain elements to the exclusion of others, which is not persuasive. For example, Applicant argues one would have had to “select TBI from Yednock”; no such selection is required, only that applying the treatment of Yednock to TBI would have been obvious. Applicant argues importing Yednock’s treatment into Muizelaar. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant again argues that the “reasoning” of the rejection could only be obtained from the instant disclosure but fails to point to any fact or reason obtained solely from the rejection. Rather, Applicant points to each fact and reasoning obtained from the prior art in the paragraph spanning p.12-13 and, while Applicant argues why the reasoning is insufficient, it demonstrates that the combination does not rely on impermissible hindsight.
Applicant argues the art was “highly unpredictable”, reiterating the argument that complement (the whole system) can have both neurotoxic and neuroprotective effects. This does not directly criticize any teaching regarding C1q specifically, which is the member at issue and which would have been reasonably predictable for the reasons set forth. There is no conflicting teaching regarding using C1q to treat TBI within the meaning of the claims while the rejection sets forth the reasons to expect success.
Applicant argues unexpected results. Applicant argues that Example 7 demonstrates that complement blockade prevents memory deficits. This example (p.83) states that C1q inhibition significantly improved recognition memory capabilities when compared with aged, injured animals, referencing figure 6. While this is a result, this does not present adequate information as to why the result was unexpected. As set forth in the rejection, inhibition of C1q was already expected to treat TBI and the response does not provide objective evidence as to the expected result of C1q inhibition and so the results cannot be deemed unexpected. Further, it is noted that the subject being “aged” is not a claim limitation, nor is the prevention of memory deficits.
In attempting to argue the results were unexpected, Applicant returns to Hammad’s statement that C1q could have a neuroprotective effect. This is addressed above. Applicant argues that C1q deficiency was associated with increased epileptogenesis and susceptibility to infection. First, this is addressed above and is not probative of an unexpected therapeutic benefit to treating TBI with C1q. Second, the instant data does not provide evidence that the instant treatment does not cause these results and so there is a lack of evidence suggesting that the instant treatment surprisingly does not result in these effects. Applicant argues the results are surprising “particularly in aged animals”; this is not a claim limitation. Surprising results must be commensurate in scope with the claims (MPEP §716.02(d)).
Applicant argues that only the instant specification teaches the relationship between C1q elevation, synaptic pathology, and cognitive decline. This is not persuasive because, for example, Yednock teaches the increase of C1q after brain injury (paragraph 97). Yednock also establishes that C1q plays a significant role in synapse loss and inhibiting C1q is a beneficial, effective treatment for diseases associated with loss of synapse or nerve connections, including ischemic injuries.
While Applicant argues Hammad expressly called for further research to determine if “complement” is neuroprotective or neurotoxic, 1) this is not specific to C1q and 2) the combination does not require absolute predictability and a mere suggestion to continue researching the complement pathway does not amount to C1q being “unexpected” in treating TBI based on the facts of record.
Applicant correctly notes that unexpected results must be considered, which has been done above. Unexpected results must also be commensurate in scope with the claims (MPEP §716.02(d)). It is Applicant’s burden to show the results were in fact unexpected (MPEP §716.02(b)). There are no direct or indirect comparison tests of what would have been expected when inhibiting the classical complement system rather than the whole of the complement system (MPEP §716.02(b)(III)). Where any unexpected properties are not shown to have a significance equal to or greater than the expected properties, the evidence may not be sufficient to rebut the evidence of obviousness (MPEP §716.02(c)(I)). Expected beneficial results (C1q inhibition treats TBI) are evidence of obviousness (MPEP §716.02(c)(II)).
Evidence pertaining to secondary considerations must be taken into account whenever present; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007).
Taking all of the evidence as a whole, including the teachings of the art, inferences of the person of ordinary skill, the arguments of Applicant, and the objective evidence in the specification, the evidence is still considered to weigh on balance in support of a conclusion of obviousness.
Regarding double patenting, Applicant argues the claims of the reference patents claim Fab fragments, not full-length antibodies. Applicant more broadly asserts that none of the references claim “a method of treating a traumatic brain injury, comprising administering to a subject a full-length anti-C1q antibody that inhibits the classical complement pathway”. Applicant references the previous arguments as to why the secondary references do not correct these deficiencies and are not persuasive for the same reasons.
Conclusion
Applicant's amendment necessitated any 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.
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/Adam Weidner/Primary Examiner, Art Unit 1675
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