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 .
DETAILED ACTION
Status of Application/Election/Restrictions
Applicant's election with traverse of Group II (claim 86), SEQ ID NO:37, SEQ ID NO:33, C1q inhibitor, antibody, traumatic brain injury, and anti-C1q antibody in the reply filed on September 11, 2025 is acknowledged. The traversal is on the ground(s) that all of the claims share the same special technical feature because i) they have a common property or activity, and have a special technical feature by administration of the same inhibitor to a subject with epilepsy; and ii) the references of Yednock (US10723788) and Block (US12122836) do not disclose an inhibitor having the common property or activity and shared significant element. This is not found persuasive because Yednock et al. (US10723788) or Block (US12122836) does teach the method of treating epilepsy using an inhibitor of classical complement pathway as recited in claim 1 for the reasons set forth in the prior office action dated 07/15/2025 (i.e. using an inhibitor of classical complement pathway, an anti-C1q antibody; see col. 15, lines 7-23 in US10723788; or using an inhibitor of classical complement pathway, stradomers; see col. 70, line 66 in US12122836). Since the 1st claimed invention has no special technical feature, it cannot share a special technical feature with the other claimed inventions.
The requirement is still deemed proper and is therefore made FINAL.
Claims 4-8, 10-17, 21-32, 35-36, 45-52, 54-61, 63-85 and 87-98 are canceled. Claims 1-3, 9, 18-20, 33-34, 37-44, 53, 62 and 86 are pending in this application. Claims 1-3, 9, 18-20, 33-34, 37-44, 53 and 62 are withdrawn with traverse (filed 09/11/2025) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on September 11, 2025.
Claim 86 is under examination in this office action.
Claim Objections
5. Claims 1-3, 9, 18-20, 33-34, 37-44, 53 and 62 are objected to because of the following informalities: the status of the claims 1-3, 9, 18-20, 33-34, 37-44, 53 and 62 is incorrect because these claims are withdrawn from consideration. Appropriate correction is required.
See MPEP 714 & 37 CFR 1.121.
“In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).”
6. Claim 86 is objected to because of the following informalities: The recitations “C1q” “C1r” and “C1s” are not unique or common abbreviations in the art. Applicants are required to spell out “C1q” “C1r” and “C1s” at the first usage. Appropriate correction is required.
Claim Rejections - 35 USC § 101
7. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 86 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) recite(s) determining a subject’s risk of developing epilepsy due to a traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome based on a correlation of different expression levels and locations of C1q, C1r or C1s in a subject in vivo when compared to a reference with the presence of epilepsy. This correlation is a consequence of natural phenomenon in the subject suffering from a traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome, which is a judicial exception. The instant claim claims determining a test subject’s risk of developing epilepsy due to a traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome based on a correlation between the presence of expression levels and location of the C1q, C1r or C1s in the test subject in vivo compared to a reference and the presence of epilepsy in patients, which is similar to the claims that were directed to a discovery of a law of nature by the Supreme Court in Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 101 USPQ2d 1961 (2012) and Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017) (Step 2A Prong 1: YES).
This judicial exception is not integrated into a practical application because the invention provides no improvement to any other technology or technical field (see MPEP 2106.05(a)) or transform into a different technology (see MPEP 2106.05(b)-(c)), does not apply or use a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition (see Vanda Memo) and does not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception (see MPEP 2106.05(e) and Vanda Memo). In addition, the claim 86 does not contain the treating step. Thus, the invention does not apply or integrate a judicial exception into a practical application such as a particular treatment or prophylaxis for a disease or medical condition (see Vanda Memo) and in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception (see MPEP 2106.05(e) and Vanda Memo) (Step 2A Prong 2: NO).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claim recites elements/steps in addition to the judicial exception(s) that are well-understood, purely conventional or routine in the relevant field, the elements/steps recited in the claim in addition to the judicial exception(s) that are insignificant extra-solution activity, e.g., are merely appended to the judicial exception(s) and amount to nothing more than a mere field of use. The additional elements “(a) administering an anti-C1q, anti-C1r, or anti-C1s antibody to the subject…..”, “(b) detecting the detectable label to measure…..” in claim 86 are insignificant extra-solution activities for collecting data and are merely appended to the judicial exception(s) and amount to nothing more than mere field of use view of Rosenthal et al. (US9708394; see col. 57, lines 45-54), MPEP 2106.05(d)-(h) and Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1355, 1362, 123 USPQ2d 1081, 1082-83, 1088 (Fed. Cir. 2017). The addition elements “(c) comparing the amount or location….to a reference, wherein the risk ….based on the comparison….to the reference” in claim 86 is a mental step, which is a judicial exception. The combination of the judicial exception with additional elements is insufficient to ensure that the claims amount to significantly more than the exception itself because these additional elements or steps are mere field of use that impose no meaningful limit on the performance of the method and are no more than well-understood, purely conventional, and routinely taken by others in order to apply the natural principle (Step2B: NO).
Thus, claim 86 is not patent eligible because the claimed invention of claim 86 is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Claim Rejections - 35 USC § 112
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 86 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 86 is indefinite because the claim recites “comparing the amount or location ….to a reference, wherein the risk of developing epilepsy is characterized based on the comparison …to the reference”. The limitation “a reference” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what a reference is and what the claimed amount and location would be. It is unclear whether an increased amount or decreased amount of the recited C1q, C1r or C1s is indicative of the risk of developing epilepsy. It is also unclear what location or what location change is indicative of the risk of developing epilepsy. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “a reference”. Since the metes and bounds are unknown, a skilled artisan cannot envision what amount, and location would be considered as “a reference” and what amount and location would be considered as “the risk of developing epilepsy recited in the claim. Thus, the claim is indefinite.
Claim Rejections - 35 USC § 112
9. 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 86 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 detecting increased expression levels of GFAP, C1q, and IBA1 in the peri-traumatic brain injury (TBI) S1 cortex and the functionally connected ventrobasal thalamus (VB) and reticular thalamic nucleus (nRT) based on in vitro immunofluorescent staining using an anti-C1q antibody M1 on coronal brain sections in an animal model of mild traumatic brain injury (mTBI) compared to control sham mice, and detecting reduced frequency in sIPSCs and smaller amplitude and lower frequency in sEPSCs in nRT and spontaneous epileptiform events including synchronized thalamic bursting and increased normalized theta power, as early as one week and up to three weeks post-mTBI in the mTBI mice implanted with chronic wireless electrocorticographic (ECoG) devices compared to control sham mice implanted with chronic wireless electrocorticographic (ECoG) devices, does not reasonably provide enablement for a method of determining a subject's risk of developing epilepsy due to a traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome using an anti-Clq, anti-Clr, or anti-Cis antibody coupled to a detectable label to detect and measure the amount or location in the subject in vivo, and comparing the detected amount or location in the subject in vivo to an undefined reference to determine the risk of developing epilepsy as broadly 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 to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)”. See MPEP § 2164.01.
Claim 86 is drawn to a method of determining a subject's risk of developing epilepsy due to a traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome, comprising:(a) administering an anti-Clq, anti-Clr, or anti-Cis antibody to the subject, wherein the anti-C lq, anti-C lr, or anti-C 1s antibody is coupled to a detectable label; (b) detecting the detectable label to measure the amount or location of Clq, Clr, or Cis in the subject; and (c) comparing the amount or location of one or more of Clq, Clr, or CIs to a reference, wherein the risk of developing epilepsy is characterized based on the comparison of the amount or location of one or more of Clq, Clr, or Cis to the reference.
The claim encompasses a method of using an anti-Clq (elected), anti-Clr, or anti-Cis antibody to detect and measure the amount or location of C1q, C1r or C1s in the subject in vivo, and using an unknown and undefined reference for comparison to determine the subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome.
The instant invention is based on findings that: i) An animal model of mild traumatic brain injury (mTBI), mTBI mice, had significantly higher GFAP, C1q, and IBA1 expression in the peri-TBI S1 cortex and the functionally connected ventrobasal thalamus (VB) and reticular thalamic nucleus (nRT) than control sham mice (Fig. 1B-1E). ii) The increased expressions of similar inflammatory markers were detected in thalamic tissue from human TBI patients (Example 2, Fig. 7). iii) There is no difference in neuron’s intrinsic membrane electrical properties and the spontaneous excitatory and inhibitory postsynaptic current (sEPSC and sIPSC) properties in the peri-TBI cortex and the VB thalamus between sham and mTBI mice implanted with chronic wireless electrocorticographic (ECoG) devices (see Table 4). But in the nRT, mTBI showed a reduced frequency in sIPSCs and a smaller amplitude and a lower frequency in sEPSCs compared to sham mice (Example 2, Fig. 2F-2G). iv) mTBI mice treated with the anti-C1q antibody M1 showed a strong reduction in inflammation and reduced neuronal loss relative to control-treated mTBI mice (Example 5, Fig. 4A-C). v) mTBI mice implanted with chronic wireless electrocorticographic (ECoG) devices had spontaneous epileptiform events that included synchronized thalamic bursting and increased normalized theta power, as early as one week and up to three weeks post-mTBI (Example 6, Fig. 14). vi) mTBI mice treated with the anti-C1q antibody M1 showed no generalized tonic-clonic seizures and no difference in frequency of epileptic events as compared to control-treated mice (Example 7, Table 5). vii) mTBI mice treated with the anti-C1q antibody M1 showed normal numbers of sleep spindles (Example 8, Fig. 16B, 16D, 16E), and less epileptic spikes than the mice treated with the isotype control (Example 8, Fig. 17B-17F).
Applicant extrapolates the above findings to the claimed method of determining a subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome by detecting and measuring the amount or location of C1q, C1r or C1s in the subject in vivo and determining the subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome based on comparisons of the amount or location of C1q, C1r or C1s to an unknown or undefined reference.
However, the reference recited in claim 86 is not limited to specific brain regions or in vitro detection methods compared to specific healthy controls set forth above. The instant claim is directed to an in vivo detection method using an anti-Clq (elected), anti-Clr, or anti-Cis antibody to detect and measure the amount or location of C1q, C1r or C1s in the subject in vivo, and using an unknown and undefined reference for comparison to determine the subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome and using an undefined amount; i.e. increased or decreased relative to an unknown amount reference as indicative of the risk of developing epilepsy or an undefined location or undefined location change as indicative of the risk of developing epilepsy.
The specification provides insufficient guidance to enable a skilled artisan to practice the claimed invention without undue experimentation because the claimed limitation “a reference” is unknown and not defined by the specification or the claim. The specification provides no guidance as to what reference is, and what specific amount or location detected in the subject in vivo relative to an unknown or undefined reference is indicative of the risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome. Applicant cannot use an unknown reference to compare the detected amount or location in a subject in vivo and then to determine another unknown of whether the subject is at risk of developing epilepsy.
Based on the specification, Applicant is enabled for detecting an increased expression level of C1q in the peri-TBI S1 cortex and the functionally connected ventrobasal thalamus (VB) and reticular thalamic nucleus (nRT) based on in vitro immunofluorescent staining on coronal brain sections from the mTBI mice compared to the control sham mice, and detecting reduced frequency in sIPSCs and smaller amplitude and lower frequency in sEPSCs in nRT and spontaneous epileptiform events including synchronized thalamic bursting and increased normalized theta power, as early as one week and up to three weeks post-mTBI in the mTBI mice implanted with chronic wireless electrocorticographic (ECoG) devices compared to control sham mice.
Based on the instant specification, the increased C1q expression detected by an in vitro immunofluorescent staining using an anti-C1q antibody M1 can only be found in specific brain regions and only the disruption of synaptic transmission in the nRT region coincides with increased C1q expression, reduced cortical inputs, and local neuronal loss in the nRT region but not in the regions of the peri-TBI cortex and the VB. Based on p. 22 of the specification, Applicant admitted that “the major long-term effect of mTBI on corticothalamic circuits involves disruption of synaptic transmission in the nRT, which coincides with increased C1q expression, reduced cortical inputs, and local neuronal loss. In contrast, neurons in the peri-TBI cortex and the VB appear normal at chronic stages post-mTBI (Table 4), suggesting that inflammation in particular, increased C1q expression in these regions is not associated with long-term dysfunction in neuronal excitability or synaptic function” (see p. 122 of the instant specification).
Based on the instant specification and the prior art, the increased C1q expression can only be detected in specific brain regions in vitro and in specific patient populations. Bellander et al. teach detecting increased expression levels of C1q, C3b and C3d in brain sections from patients with TBI compared to healthy patients by immunohistochemical staining, in situ hybridization and Western blotting in vitro (see abstract; Bellander et al., J. Neurotrauma, 2001; 18:1295-1311). Aronica et al. teach that increased levels of C1q, C3c and C3d can be detected in microglia and hippocampal neurons in human patients with temporal lobe epilepsy (TLE) based on quantitative PCR, immunochemistry staining in vitro (see abstract, Aronica et al. Neurobiol. Dise. 2007; 26:497-511). Wyatt et al. teach that increased C1q protein levels can be detected in cortical tissue from human refractory epilepsy in vitro when compared to the non-epileptic lesions (see abstract, Wyatt et al. Exp. Neurol. 2017; 295:184-193, as in IDS). Schartz et al. teach that the increased levels of C1q, C3, and iC3b can be found in the hippocampus of an animal model of pilocarpine-induced status epilepticus (SE) at 2-, 3- and 5-weeks after SE relative to control sham animals (injected with saline) in vitro (see abstract; Schartz et al. Neurobiol. Dis. 2018; 109:163-173, as in IDS).
The specification provides no well-established structural and functional correlation between the claimed reference/the claimed amount/location in the subject in vivo and the disruption of synaptic transmission in the region of nRT that coincides with the increased C1q expression, reduced corticothalamic circuits and local neuronal loss found in the nRT based on immunofluorescent staining in vitro using an anti-C1q antibody M1. The specification also provides no well-established structural and functional correlation between the claimed reference/the claimed amount/location in the subject in vivo and the increased C1q expression that is not associated with long-term dysfunction in neuronal excitability or synaptic function in the regions of peri-TBI cortex and the VB based on immunofluorescent staining in vitro using an anti-C1q antibody M1.
The specification fails to provide sufficient guidance as to what reference is and what detected amount or detected location in the subject in vivo relative to an unknown or undefined reference is indicative of the risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke, or genetic syndrome. The specification does not teach what the claimed amount reference is, or what the claimed location reference is. Thus, a skilled artisan cannot contemplate how to use the claimed method to determine whether the subject has the risk of developing epilepsy based on comparison with unknown amount reference and/or unknown location reference.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the lack of working examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the claimed invention as it pertains to a method of determining a subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome by detecting and measuring the amount or location of C1q, C1r or C1s in the subject in vivo and determining the subject’s risk of developing epilepsy due to traumatic brain injury, hypoxic brain injury, brain infection, stroke or genetic syndrome based on comparisons of the amount or location of C1q, C1r or C1s to an unknown or undefined reference.
Claim Rejections - 35 USC § 112
10. Claim 86 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claim 86 encompasses using a genus of anti-C1q (elected), anti-C1r or anti-C1s antibody for detecting the amount and location of C1q, C1r and C1s in vivo and using a genus of amount reference and a genus of location reference for comparison and determining whether the subject is at risk of developing epilepsy after traumatic brain injury (TBI) (elected), hypoxic brain injury, brain infection, stroke or genetic syndrome.
Applicant has not disclosed sufficient species for the broad genus of anti-C1q (elected) for detecting the amount and location of C1q in vivo and the broad genus of amount reference and the broad genus of location reference for comparison and determining whether the subject is at risk of developing epilepsy determining whether the subject is at risk of developing epilepsy after traumatic brain injury (TBI) (elected).
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. The specification only describes i) detecting increased expression levels of GFAP, C1q, and IBA1 in the peri-TBI S1 cortex and the functionally connected ventrobasal thalamus (VB) and reticular thalamic nucleus (nRT) based on in vitro immunofluorescent staining using an anti-C1q antibody M1 on coronal brain sections in an animal model of mild traumatic brain injury (mTBI) compared to control sham mice, and ii) detecting reduced frequency in sIPSCs and smaller amplitude and lower frequency in sEPSCs in nRT and spontaneous epileptiform events including synchronized thalamic bursting and increased normalized theta power, as early as one week and up to three weeks post-mTBI in the mTBI mice implanted with chronic wireless electrocorticographic (ECoG) devices compared to control sham mice implanted with chronic wireless electrocorticographic (ECoG) devices.
The claim is not limited to detection of C1q in the peri-TBI S1 cortex and the functionally connected ventrobasal thalamus (VB) and reticular thalamic nucleus (nRT) based on in vitro immunofluorescent staining using an anti-C1q antibody M1 and methods set forth above but also encompass detecting C1q in a genus of undefined location and comparing the detected amount and location to a genus of unknown or undefined amount reference or unknown or undefined location reference.
The specification provides no sufficient information to demonstrate or support that Applicant is in possession of the claimed method of using in vivo detection method to detect and measure the amount or location of C1q in vivo and comparing the detected amount or location of C1q in a subject in vivo to a unknown or undefined reference to determine the subject’s risk of developing epilepsy. Applicant is not in possession of detecting C1q in vivo using a genus of structurally and functionally undefined anti-C1q antibody and comparing the detected amount or detected location to a genus of undefined amount reference or undefined location reference to determine whether the subject is at risk of developing epilepsy.
Based on Applicant’s own admission on p. 22 of the specification, “the major long-term effect of mTBI on corticothalamic circuits involves disruption of synaptic transmission in the nRT, which coincides with increased C1q expression, reduced cortical inputs, and local neuronal loss. In contrast, neurons in the peri-TBI cortex and the VB appear normal at chronic stages post-mTBI (Table 4), suggesting that inflammation in particular, increased C1q expression in these regions is not associated with long-term dysfunction in neuronal excitability or synaptic function” (see p. 122 of the instant specification).
The specification provides no well-established structural and functional correlation between the claimed genus of anti-C1q antibody and the anti-C1q antibody M1 used in Examples or anti-C1q antibodies disclosed in US9708394 or other recited US patents described on p. 25 or p. 59 of the specification. The specification fails to provide sufficient description as to what structures or sequences for the claimed genus of anti-C1q antibody in order to preserve the activity of the anti-C1q antibody M1 used in Examples or anti-C1q antibodies disclosed in US9708394 or US patents to detect increased C1q expression in specific regions of peri-TBI, VB and nRT in patients with TBI.
The specification also provides no well-established structural and functional correlation between the claimed genus of reference/the claimed genus of amount/location in the subject in vivo and the disruption of synaptic transmission in the region of nRT coinciding with the increased C1q expression, reduced corticothalamic circuits and local neuronal loss found in the nRT. The specification provides no well-established structural and functional correlation between the claimed genus of reference/the claimed genus of amount/location in the subject in vivo and the increased C1q expression that is not associated with long-term dysfunction in neuronal excitability or synaptic function in the regions of peri-TBI cortex and the VB.
Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other anti-C1q antibodies that can detect increased C1q expression in the regions of peri-TBI, VB and nRT might be
Since the common characteristics/features of other anti-C1q antibodies, references of amount of C1q and brain locations and their correlation with epilepsy or disruption of synaptic transmission in the region of the nRT are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of anti-C1q antibodies, amount reference or location reference.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-C1q antibodies, amount reference or location reference, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
11. 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.
Claim Rejections - 35 USC § 103
12. 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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over Haskins et al. (US2022/0057409, published Feb 24, 2022, priority Dec 13, 2018) in view of Rosenthal et al. (US9708394, issued Jul 18, 2017, priority Jul 9, 2013) and Chen et al. (J. Neurotrauma, 2020 March 1, 37:692-705).
The rejection is based on what is enabled within the claim as set forth above under the 112(a) rejection.
Haskins et al. (US2022/0057409) teach that traumatic brain injury (TBI) is a risk factor for chronic traumatic encephalopathy (CTE) or epilepsy (see para. [0004]) and also teaches a method for detecting or diagnosing TBI, stroke or epilepsy, comprising in vitro diagnostic steps or in vivo techniques for detection of a marker comprising introducing a label agent that specifically binds the marker into a test subject, wherein the agent can be labeled with a radioactive marker or is an antibody conjugated to a detectable label that binds a temporal biomarker to detect the amount or location of the temporal biomarker in the subject by standard imaging techniques (see para. [0090]-[0092]). Haskins teaches a step of comparing the quantity of one or more temporal biomarkers to normal control to determine the injury or disease of the subject (see para. [0097]), and that the markers in biofluid include C1q (see para [0109]).
But Haskins does not explicitly teach administering an anti-C1q antibody to the test subject recited in claim 86.
Rosenthal et al. (US9708394) teach an in vivo diagnostic method comprising steps: i) administering an anti-C1q antibody, or functional fragment thereof, to an individual with a neurodegenerative disease including injury after ischemia and reperfusion, and detecting the antibody bound to a synapse of the individual, wherein the anti-C1q antibody is conjugated to a detectable label; ii) detecting and quantifying the level of C1q in synapses by positron emission tomography (PET), X-ray computed tomography, single-photon emission computed tomography (SPECT), computed tomography (CT), and computed axial tomography (CAT); iii) comparing the amount of the detected C1q to healthy controls (see col.57, line 45-col. 58, line 16).
Chen et al. tach that traumatic brain injury (TBI) induces a vigorous neuroinflammatory response and that a significant proportion of patients with TBI suffer from debilitating post-traumatic epilepsy (abstract). Chen teaches that increased expression levels of C1q can be found TBI and epilepsy, animal model of TBI induced by cortical contusion or penetrating and rotational TBI (see p. 693, 2nd col., 3rd paragraph, p. 698, figure 2) and microglial cells and hippocampal neurons in rat model of temporal lobe epilepsy (TLE) or human TLE with hippocampal sclerosis, status epilepticus (SE) (p. 699, 1st col. last paragraph to 2nd col. 1st paragraph; p. 698, Figure 2).
A person of ordinary skill in the art would have recognized that selecting and applying the known step of detecting the increased level of C1q in microglia and hippocampal neurons in patients with TBI and/or epilepsy, the known technique of in vivo diagnostic method by administering an anti-C1q antibody to a test subject and the known comparison method relative to a healthy normal subject disclosed by Rosenthal and Chen to the Haskins’ method would have yielded the predictable result of determining the subject’s risk of developing epilepsy due to TBI based on detecting the increased amount of C1q in the microglia and hippocampal neurons compared to the amount or location of C1q in a healthy control subject and resulted in an improved method.
Using and including the known step of detecting increased level of C1q in microglia and hippocampal neurons in patients TBI and/or epilepsy, the known technique of in vivo diagnostic method by administering an anti-C1q antibody to a test subject and the known comparison method relative to a healthy normal subject disclosed by Rosenthal and Chen in the Haskins’ method would detect the amount or location of C1q in the test subject suffering from TBI and determine the subject’s risk of developing epilepsy based on the increased C1q expression levels in microglial and hippocampal neurons in the subject with TBI when compared to those in the healthy normal subject, and would expand application of the Haskins’ method in purposes of diagnosis and treatment of post-traumatic epilepsy and would increase patient’s satisfaction with diagnosis of the risk of developing epilepsy due to TBI, and treatment of post-traumatic epilepsy.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known step of detecting the increased level of C1q in microglia and hippocampal neurons in patients with TBI and/or epilepsy, the known technique of in vivo diagnostic method by administering an anti-C1q antibody to a test subject and the known comparison method relative to a healthy normal subject disclosed by Rosenthal and Chen to the Haskins’ method, and yield the predictable result of determining the subject’s risk of developing epilepsy due to TBI based on detecting the increased amount of C1q in the microglia and hippocampal neurons compared to the amount or location of C1q in a healthy control subject.
Double Patenting
13. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claim 86 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 65 of copending Application No.18/230480 or claim 48 of copending Application No. 18/680437 in view of Haskins et al. (US2022/0057409), Rosenthal et al. (US9708394) and Chen et al. (2020).
Claim 65 of Application No. 18/230480 (the ‘480 Application) claims a method of determining a subject’s risk of developing a brain injury, comprising (a) administering an anti-C1q, anti-C1r or anti-C1s antibody to the subject, wherein the anti-C1q, anti-C1r or anti-C1s is coupled to a detectable label; (b) detecting the detectable label to measure the amount or location of C1q, C1r, or C1s in the subject; and (c) comparing the amount or location of one or more of C1q, C1r or C1s to a reference, wherein the risk of developing a brain injury is characterized based on the comparison of the amount or location of one or more of C1q, C1r or C1s to the reference.
Claim 48 of Application No. 18/680437 (the ‘437 Application) claims a method of determining a subject’s risk of developing a disease associated with complement activation, comprising (a) administering an anti-C1q antibody fragment to the subject, wherein the antibody fragment is coupled to a detectable label; (b) detecting the detectable label to measure the amount or location of C1q in the subject; and (c) comparing the amount or location of C1q to a reference, wherein the risk of developing a disease associated with complement activation is characterized based on the comparison of the amount or location of C1q to the reference.
The claim of the ‘480 Application or the ‘437 Application does not recite that epilepsy. While the claim of the ‘480 Application or the ‘437 Application does not teach epilepsy recited in claim 86, Haskins, Rosenthal and Chen teach this limitation and provide motivation and an expectation of success for the reasons set forth above under the 103 rejection. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known step of detecting the increased level of C1q in microglia and hippocampal neurons in patients with TBI and/or epilepsy, the known technique of in vivo diagnostic method by administering an anti-C1q antibody to a test subject and the known comparison method relative to a healthy normal subject disclosed by Haskins, Rosenthal and Chen to the method of the ‘480 Application or the ‘437 Application, and yield the predictable result of determining the subject’s risk of developing epilepsy due to TBI based on detecting the increased amount of C1q in the microglia and hippocampal neurons compared to the amount or location of C1q in a healthy control subject.
This is a provisional nonstatutory double patenting rejection.
Conclusion
14. NO CLAIM IS ALLOWED.
15. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Bellander et al. (J. Neurotrauma, 2001; 18:1295-1311) teach that detecting increased expression levels of C1q, C3b and C3d in brain sections from the patients with TBI based on immunohistochemical staining, in situ hybridization and Western blotting (see abstract).
Aronica et al. (Neurobiol. Dise. 2007; 26:497-511) teach that increased levels of C1q, C3c and C3d can be detected in microglia and hippocampal neurons in human patients with temporal lobe epilepsy (TLE) using quantitative PCR and immunochemistry staining (see abstract).
16. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
January 26, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675