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 (i.e., changing from AIA to pre-AIA ) 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 12/15/23. Claims 2-17 are pending and under examination.
Applicant is advised that should claim 3 be found allowable, claim 4 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claims 3 and 4 recite identical method steps. The only difference is in the preamble. When reading the preamble in the context of the entire claim, the recitations are not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Both methods are methods of treating chronic inflammation (step b is practiced on an identical individual) and both are methods of monitoring that treatment (steps a and c).
Thus, the preamble of the claim(s) is not considered a limitation. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 17 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing neurodegeneration caused by stroke, does not reasonably provide enablement for reducing or preventing all forms of neurodegeneration as instantly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: 1) nature of the invention, 2) breadth of claims, 3) amount of direction or guidance by the inventor, 4) relative skill of those in the art, 5) level of predictability in the art, 6) state of the prior art, 7) existence of working examples, and 8) quantity of the experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant method is drawn to treating chronic inflammation in a subject that has had a stroke. This inflammation leads to neuronal damage and neurodegeneration. However, the breadth of the claim is such that administering any anti-inflammatory will treat or prevent any neurodegeneration in the subject, regardless of the etiology of that neurodegeneration.
One such neurodegenerative disease is Alzheimer’s disease. The art currently does not recognize any drug or method that results in the complete prevention of Alzheimer’s disease. See for example Reitz (cited on form 892) that states “as the currently available drugs only slightly affect disease severity and progression, AD remains at present effectively untreatable” (p.2 C1) and Stanford (cited on form 892) that states "unfortunately, there are no currently available FDA-approved medications proven to delay or slow progression of the underlying brain degeneration and loss of synaptic connections that occurs in Alzheimer’s disease”. Where the goal is recognized as difficult and as-yet unrealized, the evidence supporting a claim that such a result is achievable must necessarily be strong.
The instant specification does not provide any working examples of prevention of any form of neurodegeneration nor does it provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. Claim 17 does not require any particular anti-inflammatory administered in any particular way and there is no reasonable expectation that, e.g., ibuprofen (an anti-inflammatory) will fully prevent Alzheimer’s disease nor even that this drug would fully prevent the neuronal damage associated with stroke. While the mechanisms disclosed in the instant specification and in the prior art teach a role for inflammatory damage after stroke and therefore there is a reasonable expectation of some reduction in stroke-associated neurodegeneration, one skilled in the art could not practice the method of the claims to achieve the result of prevention of neurodegeneration nor reduction of non-stroke related neurodegeneration.
Therefore, claim 17 is not enabled for the full scope of the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 requires measuring the level of MMP12. Claim 7, which depends from claim 2, requires this be the level of MMP12 nucleic acid or polypeptide. However, this appears to cover every possible choice. MMP12 exists as DNA (nucleic acid), RNA (nucleic acid), and the protein (polypeptide). The instant specification does not disclose an MMP12 level which is not one of those two categories and so claim 7 does not provide a further limitation.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 2-8, 13-14, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chelluboina A (“Matrix Metalloproteinase-12 Induces Blood–Brain Barrier Damage After Focal Cerebral Ischemia”; form 892) in view of Chelluboina B (“Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage”; IDS 1/13/25 citation 005) and further in view of Baier (form 892).
Please note that Chelluboina A will be referred to as “Chelluboina” while Chelluboina B will be referred to by the second author “Warhekar”.
Regarding claim 2, Chelluboina teaches middle cerebral artery occlusion (MCAO) as a model for ischemic stroke (p.3524 C1). Chelluboina teaches subjecting rats to MCAO and measuring MMP-12, e.g., p.3524 C1-2 and figure 1. Chelluboina teaches that MMP12 levels are increased in the rats that had a stroke when compared to those rats subjected to sham treatment, i.e., rats which did not have a stroke (figure 1). Chelluboina further teaches administering M-12sh (an inhibitor of MMP12 expression) two hours after ischemia (p.3525 C2), which reduced the levels of MMP12 in the ischemic brain tissue of the rat (p.3525 C2; figure 3).
M-12sh meets the instant limitations of an anti-inflammatory therapy. Warhekar also teaches that MMP12 is upregulated after focal ischemia (p.2 C1). Warhekar teaches that MMP12 degrades proteins allowing macrophages to penetrate into injured tissue during inflammation (p.5 C1) Warhekar further teaches that MMP12 enhances neuroinflammation as well as processes pro-TNFα into active TNFα, where TNFα is a known pro-inflammatory cytokine (p.5 C2). Warhekar also suggests MMP-12shRNA as a therapeutic for ischemic stroke (p.5 C2). Thus, inhibitors of MMP12, such as M-12sh, are anti-inflammation therapies.
Finally, chronic inflammation is a secondary condition caused by the initial acute ischemic stroke; see Baier, stating that “following acute stroke, an initial brain attack caused by lack of blood flow [ischemia], the blood-brain barrier [BBB] is breeched, allowing the infiltration of inflammatory molecules that trigger secondary brain cell death in the weeks and months that follow. This acerbated inflammation is the hallmark of chronic stroke” (p.2). Chelluboina teaches the ischemic stroke damages the blood-brain barrier (title; p.3523 C1). The instant specification does not have any special definition of “chronic inflammation” or “chronic”. Since disruption of the BBB allows for inflammation for weeks to months and ischemic stroke causes this disruption of the BBB, it follows that ischemic stroke leads to secondary chronic inflammation.
It would have been obvious to one of ordinary skill in the art at the time of filing to modify the method of Chelluboina to include assaying MMP12 after stroke and to administer an anti-inflammatory therapy in response to elevated levels in order to treat chronic inflammation.
One would have found it obvious to assay a sample from a subject that has had a stroke for the level of MMP12. Both Chelluboina and Warhekar teach MMP12 is increased after stroke, while Warhekar assays MMP12 after the stroke but before any intervention.
Further, one of ordinary skill in the art would have understood the significance of elevated MMP12 levels post-stroke. Chelluboina teaches MMP12 leads to acute brain damage, specifically to the blood-brain barrier, while Baier teaches that this damage to the BBB after stroke leads to infiltration of inflammatory molecules, leading to secondary damage for months after the initial stroke.
This understanding would have made it obvious to the person of ordinary skill in the art to administer an anti-inflammatory when the level of MMP12 is increased relative to the level in a subject that has not had a stroke. Warhekar demonstrates that MMP12 is increased relative to the level in a subject that has not had a stroke while both Warhekar and Chelluboina use the anti-inflammatory M12sh to attenuate the stroke damage. Given the knowledge of the role of MMP12 in neuronal damage, neuroinflammation, and secondary damage as well as the benefits of inhibiting MMP12, one would have found it obvious to administer an anti-inflammatory in order to reduce the damage caused by this inflammatory response.
Finally, it would have been obvious to apply this method to treat the chronic inflammation in a subject that has had a stroke. Chronic inflammation was known to be associated with stroke. It is noted that there is no positively recited treatment of chronic inflammation, only that the claims characterize the method as one of treating chronic inflammation. Where the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations, the preamble of the claim(s) is not considered a limitation. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02. However, to the extent that the method must treat chronic inflammation, chronic inflammation occurs after ischemic stroke as taught by Baier. Since chronic inflammation was a known problem after stroke, treatment with an anti-inflammatory would have been reasonably expected to treat that inflammation.
Regarding claim 3, both Chelluboina and Warhekar perform the MMP12 at multiple time points, making it obvious that the assay could be repeated. This is additionally true because Warhekar assays prior to drug intervention while both Chelluboina and Warhekar assay after the anti-inflammatory treatment, making it obvious that both of these are valid time points for the assay.
Regarding claim 4, this is a duplicate of claim 3 as described above. However, it would also have been obvious that the method as described herein would function to monitor treatment. It was known that MMP12 increases after stroke and it would have been obvious to treat the stroke. Repeating the assay to determine MMP12 levels would have been an obvious way to monitor the stroke treatment to observe, e.g., the effect of the treatment on the abnormally elevated levels. 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.
Regarding claim 5, both Chelluboina and Warhekar use brain tissue, making this an obvious choice. Brain tissue meets the instant claim limitation of both “cells” and “tissue”.
Regarding claim 6, both Chelluboina and Warhekar analyze ischemic stroke and so it would have been obvious to perform the method on subjects with this type of stroke.
Regarding claim 7, both Chelluboina and Warhekar use PCR, which measured levels of MMP12 nucleic acid.
Regarding claim 8, Warhekar also measures MMP13 (figure 1). One could have combined this measurement in the same way as Warhekar with predictable results.
Regarding claim 13, Warhekar measures MMP12 one day and seven days (one week) after stroke (figure 2). Chelluboina measures MMP12 after one day (p.3524 C2). Thus, it would have been obvious to measure at these time points as it was known that MMP12 was elevated at these time points. Further, both references teach other time points, e.g., 3 and 5 days. This teaches one of ordinary skill in the art that the timing of the assay may be at a number of points; selecting a particular time point would have been a matter of ordinary creativity (MPEP 2141(II)(C)). MPEP §2144.05(II)(A) states “it 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”. Such is the case here, where measurement of MMP12 will provide a relevant MMP12 measurement and the timing of such would be the “mere carrying forward” of the methods in the prior art.
Regarding claim 14, Warhekar assays at 1 day and then repeats at one week. Further, Baier teaches the post-stroke inflammation may persist for months. It would have been obvious to one of ordinary skill in the art to repeat the assay as described above. Doing so after some amount of time has passed such as one day, one week, one month, or one year would have been a matter of ordinary creativity (MPEP 2141(II)(C)) and the mere carrying forward of the prior art (MPEP §2144.05(II)(A)), particularly as Baier teaches a reason to expect the gathered data to be relevant several months after the stroke.
Regarding claim 17, this is a result that flows from the method. Administering the same drugs to the same population with the same condition will necessarily achieve the same results. Applicant's attention is directed to MPEP § 2112 (II), which states, "there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)." Further, the court has noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003). See MPEP § 2111.04).
Nevertheless, it is also noted that Warhekar teaches the neuroprotective effects of reducing MMP12 after stroke (p.4 C2), providing a reasonable expectation of achieving similar results with the above method.
Therefore, claims 2-8, 13-14, and 17 would have been obvious.
Claim(s) 9-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chelluboina A (referred to as Chelluboina) in view of Chelluboina B (referred to as Warhekar) and Baier as applied to claims 2-8, 13-14, and 17 above, and further in view of Barone (form 892).
Chelluboina, Warhekar, and Baier are discussed above and incorporated herein. The anti-inflammatory administered by Chelluboina and Warhekar is M-12sh, which downregulates the expression of MMP12. MMP12 is responsible for activating TNFα as discussed above. Failing to activate TNFα does not meet the limitation of “blocking” TNFα; however, active TNFα is described as proinflammatory and detrimental in stroke, suggesting that blocking TNFα would be beneficial.
Barone teaches administering anti-TNFα antibody neutralizes (blocks) TNFα, significantly reduces infarct size and is neuroprotective after ischemic stroke (p.1-2).
It would have been obvious to one of ordinary skill in the art at the time of filing to administer an anti-TNFα antibody to a subject that had a stroke. This is because Barone teaches this is a beneficial therapy to a subject that had a stroke.
Therefore, claims 2-11, 13-14, and 17 would have been obvious.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chelluboina A (referred to as Chelluboina) in view of Chelluboina B (referred to as Warhekar) and Baier as applied to claims 2-8, 13-14, and 17 above, and further in view of Liu (form 892).
Chelluboina, Warhekar, and Baier are discussed above and incorporated herein. These references do not teach the therapies of instant claim 12. However, as discussed above, the combination of references teaches the detrimental effects of BBB disruption, which allows inflammatory molecules to cause damage for months after an ischemic stroke. The anti-inflammatory administered by Chelluboina and Warhekar is M-12sh, which downregulates the expression of MMP12. MMP12 is responsible for activating TNFα as discussed above. Active TNFα is described as proinflammatory and detrimental in stroke, suggesting that blocking TNFα would be beneficial.
Liu uses a model of ischemic stroke (MCAO; abstract). Liu teaches metformin attenuates BBB disruption following ischemic stroke (title; abstract) and that “metformin…reduces stroke incidence and alleviates chronic inflammation” (abstract). Liu teaches that the ability of metformin to reduce BBB damage “alleviat[es] neutrophil infiltration” (abstract) and teaches that metformin “reduced TNF-α-induced inflammation” (p.2 C1).
One of ordinary skill in the art at the time of filing would have found it obvious to administer metformin as a stroke therapy. This is because Liu teaches metformin is a beneficial treatment for ischemic stroke. Further, Liu teaches metformin possesses the desirable properties discussed in Chelluboina and Warhekar, such as being anti-inflammatory, inhibiting the effects of TNF-α, and reducing BBB damage.
Therefore, claims 2-8, 12-14, and 17 would have been obvious.
Claim(s) 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chelluboina A (referred to as Chelluboina) in view of Chelluboina B (referred to as Warhekar) and Baier as applied to claims 2-8, 13-14, and 17 above, and further in view of Uphaus (form 892).
Chelluboina, Warhekar, and Baier are discussed above and incorporated herein. These references do not teach assaying the level of neurofilament light (NfL); however, these references are concerned with treating ischemic stroke. In particular, Baier teaches the long-term damage of ischemic stroke.
Uphaus teaches measuring NfL levels (abstract; figure 2) and teaches that NfL is a “valuable biomarker for functional independence 90 days after ischemic stroke and predicts cardiovascular long-term outcome” (abstract).
It would have been obvious to one of ordinary skill in the art to include assaying (measuring) NfL levels in the method of Chelluboina/Warhekar/Baier. This is because the combination of references are directed to treatment of ischemic stroke and Uphaus teaches NfL is predictive of ischemic stroke prognosis. Thus, including measurement of these levels would have been obvious for performing on any subject after such a stroke, but also would predictably provide insight into therapeutic efficacy, e.g., reduced levels of NfL are predictive of a better outcome or therapeutic benefits.
Therefore, claims 2-8 and 13-17 would have been obvious.
Conclusion
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/Adam Weidner/ Primary Examiner, Art Unit 1675