Wednesday, January 6, 2016

PTAB reverses obviousness of treating muscle-based disorders with a compound targeted at sensory neurons

Takeaway: The Examiner issued an obviousness rejection of claims to a method of using modified botox to treat urogenital-neurological disorders. One reference taught the modified toxin recited in the claims as a treatment for chronic pain. The other reference taught unmodified botox as a treatment for urogenital-neurological disorders, and also mentioned that pain was a symptom of these disorders. The Examiner used a substitution rationale and asserted that a POSITA would expect the modified (claimed) toxin to be "effective at treating chronic pain in urogenital-neurological disorders." The Board reversed, finding that the POSITA would have no reason to expect that "the opioid targeting moiety designed for nociceptive [sensory neuron] pain" would have any efficacy in treating the "muscle based urogenital­ neurological disorders" recited in the claims. (Ex parte Brin, PTAB 2015.)


Ex parte Brin
Appeal 201300250; Appl. No. 12/255,369; Tech. Center 1600
Decided:  Dec. 2, 2015

The application on appeal was directed to using a modified botulism toxin (botox) to treat sensory nerve bladder disorders, such as incontinence and chronic urinary tract infection.

A representative claim on appeal read:
     A method of treating urogenital-neurological disorder in a human, the method comprising the step of administering to the human in need thereof a therapeutically effective amount of a composition including a modified Clostridial toxin comprising
     an opioid peptide binding domain,
     a Clostridial toxin translocation domain and
     a Clostridial toxin enzymatic domain,
     wherein the urogenital-neurological disorder is selected from the group consisting of urinary incontinence, overactive bladder, detrusor dysfunction, lower urinary tract dysfunction, urinary retention and urinary hesitancy,
      wherein administration of the composition reduces a symptom of the urogenital­ neurological disorder, thereby treating the human.
The Examiner rejected the claims as obvious over Schmidt in view of Foster. Schmidt was used to show a method of treating urogenital-neurological disorders with (unmodified) botulinum toxin. Foster was used to show the modified toxin (having specific domains) recited in the claim.

The Examiner used a substitution rationale, asserting that Foster's modified toxin would provide several benefits mentioned in Foster (e.g., good efficacy, low dosage). "It would have been expected, absent evidence to the contrary, that the modified toxin would be effective at treating chronic pain in urogenital-neurological  disorders." The Examiner noted that Schmidt described patients with a urogenital-neurological disorder as experiencing pain, and that Foster's modified toxins were used to treat chronic pain.

The Applicant appealed the obviousness rejection and argued the prima facie case was insufficient. The Applicant focused on the different "mechanisms of action" in Schmidt and Foster. Schmidt's toxin affected a motor neuron, while Foster's modified toxin affected a sensory neuron. Thus, Schmidt treated a urogenital-neurological disorder by paralyzing a muscle, while Foster controlled pain by targeting sensory nerves (no effect on muscle).
[W]here there are two references being combined, each of which show the treatment of different diseases or conditions by a different mechanism of action, there is no reasonable expectation of success. Even an "obvious to try" approach would be insufficient to make out the prima facie case of obviousness. (See, e.g., In re May, 574 F.2d 1082, 1094, (CCPA 1978) and In re Schechter, 205 F.2d 185, 191, (CCPA 1953).)
Finally, the Applicant used these differences to rebut the Examiner's substitution rationale:
The Examiner is arguing that the respective methods of treating chronic pain by blocking the neuron are similar to blocking a receptor that activates a muscle by means of a neuron that provides a neurotransmitter such as acetylcholine. But the Examiner has provided no reference to show that these methods are similar. And, in fact, since the mechanisms of action are different, they are not similar.
In the Answer, the Examiner noted that the claims did not recite "different mechanisms of action." The claims did recite "reducing a symptom of a urogenital-neurological disorder." The Applicant's spec listed pain as a symptom of such disorders, and both Schmidt and Foster taught their toxin was useful to treat pain.

The Examiner was not persuaded by the Applicant's attack on the substitution rationale, since "the features upon which applicant relies (i.e., "mechanisms of action) are not recited in the rejected claim(s)." The Examiner maintained there was a reasonable expectation for the modified toxin to effectively treat chronic pain "absent convincing evidence to the contrary."

The Applicant did not file a Reply Brief.

The Board reversed the obviousness rejection as not being supported by the references. While the Examiner focused on pain treatment as a reason to combine the references, and asserted a reasonable expectation of success, the Board disagreed.
     Pain is not one of the recited conditions in claim 1. Foster's modified clostridium toxin would have been expected to treat pain, not the conditions recited in claim 1. We therefore agree with Appellants that there would have been no reason, based on Foster, to expect that a modified clostridium toxin with an opioid targeting moiety would have any efficacy on muscle based urogenital­ neurological disorders "selected from the group consisting of urinary incontinence, overactive bladder, detrusor dysfunction, lower urinary tract dysfunction, urinary retention and urinary hesitancy" (Claim  1). Schmidt also provides no reason to modify the clostridial toxin with an opioid targeting moiety because Schmidt is focused on treatment of voiding dysfunction, not pain. Neither Foster nor Schmidt provide any suggestion that an opioid targeting moiety designed for nociceptive pain would have any efficacy treating the conditions recited  in claim 1.
My two cents: The Applicant was wise not to frame this as a non-analogous art argument. The references were probably similar enough to be analogous, yet the Applicant successfully argued that the differences undermined the rationale to combine.

The Applicant leveraged a basic distinction between the two references – targeting muscles vs. targeting sensory nerves – into two slightly different arguments. One, the Examiner's substitution rationale was flawed because the treatment mechanisms were different, not similar.  Two, a POSITA reading the references would not expect the modified botox to effectively treat the claimed disorders.

The Applicant was wise to address substitution, because the Examiner brought it up. And I'm not surprised to see a no-expectation-of-success argument, since biotech cases seem to lend themselves to this. Not so in electronics, computers, and mechanical cases, since components (functional and structural) are generally expected to work in combination.

However, even when working in these technologies, you sometimes do find basic differences between the references, analogous to sensory vs motor neuron. If so, you might use these differences to craft a slightly different argument, basically explaining how/why wouldn't make sense for a POSITA to combine because of these differences.

Another way of thinking about this case is that the connection between the two references was too attenuated. One described treating chronic pain with the modified toxin, the other with treating nerve-based urological disorders with the unmodified toxin. The connection between the two was pain, in that the primary reference mentioned pain as a symptom of the treated nerve-based urological disorders. The Examiner reasoned that the claims recited "administration of the composition reduces a symptom of the urogenital­ neurological disorder", and pain was a symptom, so they were combinable. But the way I see it, the Examiner used pain as an intermediary to jump from the primary reference to the secondary. I'm not sure this was part of the Board's reasoning.

Here's something that I really don't understand about this case. The original claims recited "treating urogenital-neurological disorder." The Applicant narrowed during prosecution to include a specific set of disorders: "urinary incontinence," "overactive bladder," and four others. The Applicant didn't  mention this limitation in the response or the Appeal Brief. The Examiner failed to address it in both the Final Office Action and the Answer. And the Board mentioned this set of disorders in its obviousness analysis, but did not make a finding that the reference did (or did not) disclose the feature.


  1. Interesting that MPEP 2143.01V and 2143.01VI were not raised. Either, or both, seem relevant to the analysis.

    1. Dr. Yarus, thanks for your input.

      You're referring to "Proposed Modification Cannot Render the Prior Art Unsatisfactory for Intended Purpose" and "Cannot Change the Principle of Operation of a Reference."

      Yes, it does seem one or both of these arguments might apply to the fact pattern in Ex parte Brin. And I think these more specific arguments are in fact more common than the higher-level (more generic) argument made by the Applicant here.

      The best approach ks probably to pick the most specific argument that fits your facts. But in the end, legal arguments based on technical differences are a good approach to obviousness, regardless of how you frame them.

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