pH Limitation Renders Ophthalmic Formulation Patentable

Since the Supreme Court’s 2007 decision in KSR v. Teleflex[1], and its emphasis on a “finite number” of “predictable solutions,” Examiners have increasingly relied on the notion of routine optimization to support their prima facie cases of obviousness.  The seminal case for routine optimization in the chemical arts is In re Aller[2], but that case was rendered more than 60 years ago, and has had very little judicial follow-up.  A recent decision by the Patent Trial and Appeals Board (the “Board”) in Ex Parte Crockford[3] might portend a reversal to this trend.

Ex Parte Crockford involved a method of using Thymosin β4 to treat dry eye in an ophthalmic formulation defined principally by pH.  Independent claim 1 recited:

1. A method of treating dry eye syndrome in a subject suffering from dry eye syndrome, comprising administering to the subject an ophthalmically acceptable composition twice per day, wherein said composition has a pH of about 6.8-8.1 and comprises an isolated peptide agent comprising amino acid sequence LKKTET (SEQ ID NO.: 1) or Thymosin β4 (Tβ4), wherein said peptide agent is present in said aqueous medium at a concentration within a range of about 0.001 -- 1,000 mg/ml.

The prior art also described a method of treating dry eye using Thymosin β4, but was silent regarding a suitable pH. To remedy this defect the Examiner argued routine optimization, stating:

“a person of ordinary skill in this art would have considered … the determination of a proper pH for a composition that is topically applied to the eye to be merely a matter of judicious selection and routine optimization … a neutral pH of approximately 7.0 would be an obvious and desirable physiological choice for such in vivo administration.”

The Board acknowledged that routine optimization based on an Examiner’s common sense could support a prima facie case of obviousness when the technology was straightforward and predictable, but concluded that a documentary record in support of the argument was necessary when the technology was not predictable. 

“[A]n analysis of obviousness … may include recourse to logic, judgment, and common sense available to the person of ordinary skill that do not necessarily require explication in any reference or expert opinion.” However, in cases that applied common sense “to supply a limitation that was admittedly missing from the prior art, the limitation in question was unusually simple and the technology particularly straightforward.”

In art areas such as the chemical arts, where the technology is much more unpredictable, the Board found that it is inappropriate to apply common sense and routine optimization to support a prima facie case of obviousness. For support, the Board cited Allergan v. Sandoz[4] (“the Court finds that ophthalmic formulation is an unpredictable art”), and Eisai v. Dr. Reddy’s[5] (“To the extent an art is unpredictable, as the chemical arts often are, KSR’s focus on these ‘identified, predictable solutions’ may present a difficult hurdle because potential solutions are less likely to be genuinely predictable”).

The Board also emphasized the need for documentary evidence to maintain the integrity of the examination process:

“although this Board has subject matter expertise, the Board cannot accept general conclusions about what is ‘basic knowledge’ or ‘common sense’ as a replacement for documentary evidence for core factual findings in a determination of patentability. … To hold otherwise would be to embark down a slippery slope which would permit the examining process to deviate from the well-established and time-honored requirement that rejections be supported by evidence. It would also ultimately render the process of appellate review for substantial evidence on the record a meaningless exercise.” [citation and quotations omitted]

The Board also noted that the Manual of Patent Examining Procedure required documentary evidence of routine optimization whenever the rejection was properly traversed, citing MPEP § 2144.03(C) (“If applicant adequately traverses the examiner’s assertion of official notice, the examiner must provide documentary evidence in the next Office action if the rejection is to be maintained”).

The Board found that the Examiner had failed to “establish an evidentiary basis to support a conclusion” of routine optimization, and failed to support a prima facie case of obviousness.  The rejection was reversed.


[1] KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).

[2] In re Aller, 220 F.2d 454 (CCPA 1955).

[3] Ex parte Crockford and Goldstein, 2017 Pat. App. LEXIS 8911 (PTAB 2017).

[4] Allergan, Inc. v. Sandoz Inc., 2014 WL 12622277 at *33 (E.D. Tex. 2014).

[5] Eisai Co. v. Dr. Reddy’s Ltd., 533 F.3d 1353, 1359 (Fed. Cir. 2008).